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Aberrant activation of fibroblast growth factor receptors (FGFRs) contributes to the development and progression of multiple types of cancer. Although many FGFR inhibitors have been approved by the FDA, their long-term therapeutic efficacy is hampered by acquired resistance to gatekeeper mutations and low subtype selectivity. FGFR2 has been found to be frequently amplified or mutated in many tumors. In this study, we designed several PROTACs with different E3 ligands based on LY2874455. By screening the length of the linker and the binding site in various degraders, we obtained a novel and highly efficient FGFR2-selective degrader 28e (DC 50 = 0.645 nM, DC max = 86 %). Compound 28e selectively degraded FGFR2 and essentially avoided degradation of FGFR1,3,4 isoforms (DC 50 > 300 nM). Compound 28e significantly inhibited the proliferation of FGFR2-overexpressing cell lines, including KATOIII, SNU16, and AN3CA (IC 50 = 0.794 nM/0.207 nM/4.626 nM), comparable to parental inhibitors. At the same time, the preferred compound showed superiority over the parental inhibitor in kinase inhibitory activity against the gatekeeper mutant isoform FGFR2V564F (IC 50 = 0.121 nM). In summary, we identified 28e as a novel selective degrader of FGFR2 with high potency and high potential to overcome resistance to gatekeeper mutation. The discovery of 28e provides new evidence for the strategy of pan-inhibitor-based development of selective degrading agents. [Display omitted] • A series of novel FGFR2-selective degraders were designed and synthesized based on pan-FGFR inhibitor. • 28e exhibited the ability to efficiently degrade FGFR2 isoform with DC 50 of 0.645 nM. • 28e selectively degraded FGFR2 isoform but not FGFR1/3/4 isoforms. • 28e had the potential to overcome the FGFR2V564F gatekeeper resistance mutation. [ABSTRACT FROM AUTHOR]

[Display omitted] • New linear and cyclic arylsulfonamides were synthesized and characterized. • Significant inhibition against tumor expressed hCA IX/XII isoforms was detected. • Docking simulations suggested the poses into hCA IX and hCA XII cavities. A small series of arylsulfonamide derivatives was designed and synthesized to study linear and cyclic inhibitors targeting human Carbonic Anhydrases (hCAs EC 4.2.1.1) as essential enzymes regulating (patho)-physiological processes. Particularly, the synthesis of these ten compounds was inspired to the well-known arylsulfonamides having flexible or constrained linkers able to maintain the two crucial moieties, anchoring zinc group and hydrophobic tail, in the optimized orientation within CA cavities of tumor-expressed isoforms hCA IX and hCA XII. The synthesized imine derivatives and related cyclic 1,3-thiazin-4-ones were screened in a stopped-flow carbon dioxide hydrase assay and proved to be effective inhibitors against hCA IX and hCA XII isoforms with K i values ranging of 3.7–215.7 nM and 5.7–415.0 nM, respectively. Molecular docking studies of both series of arylsulfonamides were conducted to propose their binding mode within hCA IX and hCA XII active sites thus highlighting their distinct ability to occupy the two catalytic cavities. Moreover, the 4-[(3-cyanophenyl)methylidene]aminobenzene-1-sulfonamide 7 proved to reduce the cell viability of breast carcinoma (MCF-7) and colon rectal carcinoma (HCT-116) human cell lines under the fixed doses of 10 μM. These results encouraged us to continue our efforts in developing potent and efficient arylsulfonamides targeting hCA IX and hCA XII isoforms. [ABSTRACT FROM AUTHOR]

Ferroptosis is a new type of programmed cell death characterized by iron-dependent lipid peroxidation, during which glutathione peroxidase 4 (GPX4) plays an essential role and is well-recognized as a promising therapeutic target for cancer treatment. Although some GPX4 degradation molecules have been developed to induce ferroptosis, the discovery of GPX4 degraders with hydrophobic tagging (HyT) as an innovative approach is more challenging. Herein, we designed and synthesized a series of HyT degraders by linking the GPX4 inhibitor RSL3 with a hydrophobic and bulky group of adamantane. Among them, compound R8 is a potent degrader (DC 50 , 24h = 0.019 μM) which can effectively degrade GPX4 in a dose- and time-dependent manner. Furthermore, compound R8 exhibited superior in vitro antitumor potency against HT1080 and MDA-MB-231 cell lines with IC 50 values of 24 nM and 32 nM respectively, which are 4 times more potent than parental compound RSL3. Mechanistic investigation evidenced that R8 consumes GPX4 protein mainly through the ubiquitin proteasome (UPS) and enables to induce the accumulation of LPO, thereby triggering ferroptosis. Our work presented the novel GPX4 degrader of R8 by HyT strategy, and provided a promising pathway of degradation agents for the treatment of ferroptosis relevant diseases. [Display omitted] • The synthesis and SAR analysis of varieties of GPX4 degraders with hydrophobic tags were performed. • Compound R8 with flexible alkane chain showed remarkable protein degradation activity with a DC 50 value at nanomolar level. • R8 induced a strong ferroptotic death on multiple cancer cells evidenced by LPO flow cytometry. • R8 could decrease GPX4 protein mainly through the ubiquitin proteasome. [ABSTRACT FROM AUTHOR]

[Display omitted] The reactions between Ph 3 As and ω-bromoalkanoic acids with the length of polymethylene fragment n = 5, 7, 9 afford quaternary arsonium salts. Their treatment with alkali gives biologically active arsenobetaines. Solvent-free reactions of Ph 3 P or Ph 3 As with 2,3-dibromopropionic acid lead to the corresponding arsonium and phosphonium salts bearing (CH 2) 2 COOH substituent. [ABSTRACT FROM AUTHOR]

The antitumor activity of Ti(IV)-based compounds put them in the spotlight for cancer treatment in the past, but their lack of stability in vivo due to a high rate of hydrolysis has hindered their development as antitumor drugs. As a possible solution for this problem, we have reported a synthesis strategy through which we combined a titanocene fragment, a tridentate ligand, and a long aliphatic chain. This strategy allowed us to generate a titanium compound (Myr-Ti) capable of interacting with albumin, highly stable in water and with cytotoxic activity in tumor cells[1]. Following a similar strategy, now we report the synthesis of a new compound (Myr-TiY) derived from titanocene Y that shows antitumoral activity in a cisplatin resistant model with a 50% inhibitory concentration (IC50) of 41–76 μM. This new compound shows high stability and a strong interaction with human serum albumin. Myr-TiY has a significant antiproliferative and proapoptotic effect on the tested cancer cells and shows potential tumor selectivity when assayed in non-tumor human epithelial cells being more selective (1.3–3.8 times) for tumor cells than cisplatin. These results lead us to think that the described synthesis strategy could be useful to generate compounds for the treatment of both cisplatin-sensitive and cisplatin-resistant cancers. New titanium complex containing a titanocene Y fragment, a tridentate ligand, and a long aliphatic chain that facilitates a non-covalent interaction with albumin. This compound shows tumor cell specificity and improved antitumor activity against platinum resistant human cancer cell lines. [Display omitted] • A novel Ti(IV) drug with cytotoxic activity against cisplatin resistant tumor cells. • Titanocene Y derivative interacts non-covalently with human serum albumin. • Albumin interaction may take place through a long aliphatic chain. [ABSTRACT FROM AUTHOR]

Herein we demonstrate a new strategy by introducing Se atom with strong polarization effects to obtain highly bioactive organoselenium with electrophilic center. Organoselenium interact with Cys16 and Thr18 of PDGFB in malignant osteosarcoma MG63 cells through non-covalent bond, which further block the activation of intracellular AKT/JNK and downstream signaling pathways to promote cancer cells apoptosis. [Display omitted] • Organic selenium with high bioactivity electrophilic center was synthesized. • Org-Se can target PDGFB protein in MG63 cells and promote apoptosis. • Org-Se combined with radiotherapy can promote apoptosis of MG63 cells. Growth factor-like proteins play an important role in promoting oncogenesis. Therefore, designing specific inhibitors of such targets would facilitate the development of targeted drugs with low toxicity. However, low affinity and poor specificity between drugs and target proteins always affect the selectivity and action efficacy. Herein we demonstrates a new strategy by introducing selenium (Se) atom with strong polarization effects to obtain highly bioactive organoselenium with electrophilic center. The results of target-capturing analysis reveals that organoselenium interact with Cys16 and Thr18 of the platelet-derived growth factor B (PDGFB) protein in malignant osteosarcoma MG63 cells through non-covalent bond, thus inhibiting the expression and activity of PDGFB, which further block the activation of intracellular protein kinase B/c-Jun N-terminal kinases (AKT/JNK) and downstream signaling pathways to promote cancer cells apoptosis. Taken together, we have developed a novel strategy by introducing Se-based electrophilic centers for the development of targeted therapeutic agents for malignant tumors. [ABSTRACT FROM AUTHOR]

Covalent organic frameworks (COFs) have generated interest as promising tools for reactive oxygen species (ROS) -mediated therapy owing to designable structures and diversified modification sites. However, the ordered porous structure of COFs and their multiple catalytic sites on the enhancement of ROS-mediated therapy of cancers have attached little attention. Here, we synthesized a nanosonosensitizer named FeTPD@GOx, consisting of the ferriporphyrin-based COF (Fe-COF) loaded with glucose oxidase (GOx) for pore-enhanced ROS-mediated therapy in which GOx catalyzed glucose to H 2 O 2 while Fe3+/Fe2+ cycle catalyzed H 2 O 2 to O 2 and ·OH. The H 2 O 2 /O 2 self-supply cycle inside the pores of COFs enhanced the generation of abundant ROS in situ upon ultrasound (US) irradiation. The mechanism examination revealed that the opening pore channels of COFs not only could catch O 2 with the rapid exchange for O 2 and 1O 2 , but also provided more accessible Fenton reaction sites to iron ions for more ·OH generation, enhancing the efficacy of sonodynamic therapy (SDT) and chemodynamic therapy (CDT). In vivo antitumor evaluation revealed that FeTPD@GOx can not only inhibit the growth of the proximal tumor effectively but also display superior antitumor efficiency to the distant tumor upon US irradiation. Our work, which utilizes the porous structure, multiple catalytic sites, and GOx loading of COFs to hold O 2 , thereby promoting gas exchange, realizing sequential catalytic reactions, amplifying ROS generation, and enhancing synergistic effect of SDT and CDT for ROS-mediated therapeutic efficacy, offers prospects for applications of COFs in biomedical fields. [Display omitted] • A nanosonosensitizer named FeTPD@GOx is synthesized for relative oxygen species (ROS)- mediated therapy. • The porous structure of COF can enhance 1O 2 and ·OH for sonodynamic therapy (SDT) and chemodynamic therapy (CDT). • In vivo antitumor evaluation showed that FeTPD@GOx can inhibit the growth of the both two side tumors upon US irradiation. [ABSTRACT FROM AUTHOR]

2-polyhydroxyalkyl-1 H -imidazo[4,5-f][1,10]phenanthrolines (aldo -imidazophenanthrolines, aldo -IPs) with conformationally flexible chiral chains as potential antitumor agents. [Display omitted] A series of 1 H -imidazo [4,5-f][1,10] phenanthroline derivatives functionalized at 2-position with chiral, and conformationally flexible polyhydroxy alkyl chains derived from carbohydrates (alditol-based imidazophenanthrolines, aldo -IPs) is presented herein. These novel glycomimetics showed relevant and differential cytotoxic activity against several cultured tumor cell lines (PC3, HeLa and HT-29), dependent on the nature and stereochemistry of the polyhydroxy alkyl chain. The mannose-based aldo -IP demonstrated the higher cytotoxicity in the series, substantially better than cisplatin metallo-drug in all cell lines tested, and better than G-quadruplex ligand 360A in HeLa and HT29 cells. Cell cycle experiments and Annexin V-PI assays revealed that aldo -IPs induce apoptosis in HeLa cells. Initial study of DNA interactions by DNA FRET melting assays proved that the aldo -IPs produce only a slight thermal stabilization of DNA secondary structures, more pronounced in the case of quadruplex DNA. Viscosity titrations with CT dsDNA suggest that the compounds behave as DNA groove binders, whereas equilibrium dialysis assays showed that the compounds bind CT with K a values in the range 104–105 M−1. The aldo -IP derivatives were obtained with synthetically useful yields through a feasible one-pot multistep process, by aerobic oxidative cyclization of 1,10‐phenanthroline‐5,6‐diamine with a selection of unprotected aldoses using (NH 4) 2 SO 4 as promoter. [ABSTRACT FROM AUTHOR]

Syntheses and characterization (1H &13C NMR and CHN) of four new thiosemicarbazone derivatives (1 – 4) are reported. The molecular structures of compounds 1 – 4 were determined using single crystal X-ray crystallographic technique. Cytotoxic effect of all the compounds was determined against three cancerous (PANC-1, HCT 116 and MCF-7) and one non-cancerous (NIH/3T3) cell lines. All the compounds remained safe against non-cancerous cells (IC 50 > 500 μM) but induced significant cytotoxicity in the cancerous cell lines. Importantly, compounds 2 and 4 showed excellent cytotoxicity (IC 50 = 10.0 and 0.7 μM against PANC-1; 14.9 and 9.4 μM against HCT 116; 14.3 and 15.8 μM against MCF-7 for 2 and 4 respectively). Based on the results it can be concluded that the thiosemicarbazone derivatives (2 and 4) can be further studied in detail for the purpose of chemotherapeutic drug development. [ABSTRACT FROM AUTHOR]

Ecteinascidin 743 (Et-743), also known by the trade name Yondelis®, is the pioneering marine natural product to be successfully developed as an antitumor drug. Moreover, it is the first tetrahydroisoquinoline natural product used clinically for antitumor therapy since Kluepfel, a Canadian scientist, discovered the tetrahydroisoquinoline alkaloid (THIQ) naphthyridinomycin in 1974. Currently, almost a hundred natural products of bistetrahydroisoquinoline type have been reported. Majority of these bistetrahydroisoquinoline alkaloids exhibit diverse pharmacological activities, with some family members portraying potent antitumor activities such as Ecteinascidins, Renieramycins, Saframycins, Jorumycins, among others. Due to the unique chemical structure and exceptional biological activity of these natural alkaloids, coupled with their scarcity in nature, research seeking to provide material basis for further bioactivity research through total synthesis and obtaining compound leads with medicinal value through structural modification, remains a hot topic in the field of antitumor drug R&D. Despite the numerous reviews on the total synthesis of bistetrahydroisoquinoline natural products, comprehensive reviews on their structural modification are apparently scarce. Moreover, structural modification of bioactive natural products to acquire lead compounds with improved pharmaceutical characteristics, is a crucial approach for innovative drug discovery. This paper presents an up-to-date review of both structural modification and activity of bistetrahydroisoquinoline natural products. It highlights how such alkaloids can be used as antitumor lead compounds through careful chemical modifications. This review offers valuable scientific references for pharmaceutical chemists engaged in developing novel antitumor agents based on such alkaloid modifications, as well as those with such a goal in future. [Display omitted] • Bistetrahydroisoquinoline alkaloids represent a huge reservoir of new pharmaceuticals. • Ecteinascidin 743 (Et-743) is the first marine natural product to be successfully developed as an antitumor drug. • The structural modification of such bistetrahydroisoquinoline natural products has always been challenging. • Structural modification ofnatural products to acquire lead compoundsis a crucial approach fordrug discovery. • This paper presents an up-to-date review of structural modification of bistetrahydroisoquinoline alkaloids. [ABSTRACT FROM AUTHOR]

The development of optically pure drugs is the trend of new drugs research. Searching for optically pure metallodrugs against cancer has not been taken seriously. [CuL 4 Cl]Cl·2CH 2 Cl 2 ·H 2 O (1) and [CuL 4 Br]Br·2CH 2 Cl 2 (2) (L = 2-amino-5-dehydroabietyl-1,3,4-thiadiazole), two rosin-derivative based optically pure chiral copper(II) complexes, are rationally synthesized as potential anticancer agents. 1 exhibits effective in vitro and in vivo anticancer activities and tolerable toxicities. 1 promotes MCF-7 cell death by combination of cell arrest at G1 phase, apoptosis (both extrinsic and intrinsic apoptotic pathways), anti-metastasis, anti-angiogenesis, damage of DNA, protein and lipid, and autophagy mediated by the oxidative stress which is confirmed by ROS generation and intracellular glutathione depletion assays. 1 can be identified as a lead anticancer molecule of therapeutic importance. This work may offer insights into the design and mechanism study of multifunctional optically pure metal-based anticancer candidates derived from natural products. Image 1 • Rationally design optically pure chiral copper(II) complexes for application. • The anticancer complex shows high efficiency, low toxicity and high selectivity. • Exhibits good anti-metastasis and anti-angiogenesis ability in vitro. • The chiral copper(II) complex has good prospect of application potential. [ABSTRACT FROM AUTHOR]

TMCA (3,4,5-trimethoxycinnamic acid) ester and amide are privileged structural scaffolds in drug discovery which are widely distributed in natural products and consequently produced diverse therapeutically relevant pharmacological functions. Owing to the potential of TMCA ester and amide analogues as therapeutic agents, researches on chemical syntheses and modifications have been carried out to drug-like candidates with broad range of medicinal properties such as antitumor, antiviral, CNS (central nervous system) agents, antimicrobial, anti-inflammatory and hematologic agents for a long time. At the same time, SAR (structure-activity relationship) studies have draw greater attention among medicinal chemists, and many of the lead compounds were derived for various disease targets. However, there is an urgent need for the medicinal chemists to further exploit the precursor in developing chemical entities with promising bioactivity and druggability. This review concisely summarizes the synthesis and biological activity for TMCA ester and amide analogues. It also comprehensively reveals the relationship of significant biological activities along with SAR studies. Image 1 • 3,4,5-Trimethoxycinnamic acid (TMCA) derivatives show applications in different pathophysiological conditions due to its privileged structural scaffolds. • Natural derived TMCA analogues and chemically modified TMCA ester and amide analogues and their bioactivities are focused in this review. Additionally, it also comprehensively summarized the relationship of significant biological activities along with SAR studies of synthetic TMCA derivatives. [ABSTRACT FROM AUTHOR]

• The first examples of a new series of antitumor nucleoside analogues are described. • C-nucleosides with a xylose sugar ring were synthesized and characterized. • Compound 7 displayed a micromolar antiproliferative activity. The synthesis of a xylo -C-nucleoside containing pyrrolo[2,1-f][1,2,4]triazin-4-amine as nucleobase along with that of its 1′-cyano analogue is described. Among different experimental conditions explored in order to optimize a key debenzylation step in the presented synthetic route, it was found that palladium catalyzed hydrogen transfer allowed for obtaining the target compounds in good yields. The resulting mixture of epimers was separated and each was characterized by NOESY NMR experiments. In vitro antiproliferative assays showed that the 1′-unsubstituted analogue was active against a panel of tumor cell lines such as the human leukemia HL-60 (IC 50 = 1.9 µM) and lung cancer NCI-H460 (IC 50 = 2.0 µM) cells. [ABSTRACT FROM AUTHOR]

Abstract MutT homologue 1 (MTH1) protects the nucleotide pool from oxidative stress by hydrolyzing oxidized nucleoside triphosphates and prevents their incorporation into DNA. Cancer cells are dependent on the MTH1 activity for survival due to the high-level of reactive oxygen species in cancer cells; therefore, MTH1 is considered to be a novel target for treatment of various cancers. Here, we show by X-ray crystallographic screening using an in-house cocktail library that α-mangostin, a natural xanthone from mangosteen pericarp, binds to the active site of MTH1. A subsequent inhibition assay revealed that 3-isomangostin, a cyclized derivative of α-mangostin, was the most potent MTH1 inhibitor, with an IC 50 value of 0.052 μM. Detailed structural analyses of the MTH1-3-isomangostin complex showed the novel binding mode of 3-isomangostin. Our results demonstrate that X-ray crystallographic screening is useful for the lead discovery for MTH1, and suggest that 3-isomangostin would be an attractive chemical tool for the development of anticancer agents. Graphical abstract Image 1 Highlights • X-ray crystallographic screening identified α-mangostin as an MTH1 inhibitor. • 3-isomangostin present strong MTH1 inhibitory activity. • Crystallographic analysis revealed the novel binding mode of 3-isomangostin. [ABSTRACT FROM AUTHOR]

Abstract Five new mixed ligand metal complexes were synthesized by the reaction of Zn(II), Zr(IV), Ce(III), Th(IV) and U(VI) with ofloxacin (HOfl) and 2,2′-bipyridine (Bipy) in presence of NaOH with 1:1:1:1 M ratio. The chelation possibility of the HOfl and Bipy towards metal ions has been proposed in the light of elemental analysis, molar conductance, spectral (mass, IR, UV–Vis. and 1H NMR), magnetic and thermal studies. Infrared spectra suggest that ligands interact with metal ions as bidentate. Electronic and magnetic data proposed the octahedral structure for all complexes. The experimental studies were complemented by quantum chemical calculation. DFT calculations were carried out and ΔE for compounds in LUMO and HOMO was evaluated and indicated that the U(VI) complex with small energy gap value ΔE (0.168eV), is more reactive than all complexes. The antimicrobial activity of the complexes against various microorganisms was tested and the in vitro anticancer activity against breast (MFC7) and Colon (HCT-116) cell lines was also screened. Graphical abstract A new series of Zn(II), Zr(IV), Ce(III), Th(IV) and U(VI) metal complexes derived from ofloxacin and 2,2′-bipyridine have been synthesized and characterized. The chemical formulas, structures, antimicrobial and antitumor behavior as well as DFT were investigated. Image 1 Highlights • Five new complexes of ofloxacin and 2,2′-bipyridine were prepared and characterized. • The antimicrobial activity and in vitro cytotoxicity of ligands and complexes were evaluated. • The structure of all complexes was investigated using DFT and the nature of HOMO and LUMO were theoretically studied. [ABSTRACT FROM AUTHOR]

Abstract Microtubule-targeting agents (MTAs) are a class of clinically successful anti-cancer drugs. The emergence of multidrug resistance to MTAs imposes the need for developing new MTAs endowed with diverse mechanistic properties. Benzoxazepines were recently identified as a novel class of MTAs. These anticancer agents were thoroughly characterized for their antitumor activity, although, their exact mechanism of action remained elusive. Combining chemical, biochemical, cellular, bioinformatics and structural efforts we developed improved pyrrolonaphthoxazepines antitumor agents and their mode of action at the molecular level was elucidated. Compound 6j , one of the most potent analogues, was confirmed by X-ray as a colchicine-site MTA. A comprehensive structural investigation was performed for a complete elucidation of the structure-activity relationships. Selected pyrrolonaphthoxazepines were evaluated for their effects on cell cycle, apoptosis and differentiation in a variety of cancer cells, including multidrug resistant cell lines. Our results define compound 6j as a potentially useful optimized hit for the development of effective compounds for treating drug-resistant tumors. Graphical abstract Image 1 Highlights • We explored structure-activity relationships for a novel series of MDAs. • The crystal structure of compound 6j in complex with tubulin was solved. • Binding to isolated tubulin was evaluated for the most promising derivatives. • Compound 6j showed potent proapoptotic activity on a variety of cancer cell lines. • The best performing compounds were assessed on cell differentiation and autophagy. [ABSTRACT FROM AUTHOR]

Abstract Ultrafine single-chain tadpole polymers (SCTPs), containing an intrachain crosslinked globule and a pH-sensitive linear polymer chain, have been synthesized. Self-assembly of these polymers depends on the linear block length and the pH, at which the polymer is assembled. Although the SCTPs themselves exhibit a size that is consistent with a single-chain species, the self-assembled SCTPs were found to be substantially larger. Since the transition between these two structures is reversibly dependent on pH, we explored the possibility of utilizing these assemblies to achieve deep tissue penetration in tumors. Our results indicate that there is indeed a pH-dependent deep tissue penetration in ex vivo tumor multicellular spheroids. Moreover, the multi-tadpole assemblies (MTAs) can stably encapsulate hydrophobic molecules, which have been used to encapsulate paclitaxel (PTX). These PTX/MTAs show excellent therapeutic efficacy and biosafety in 4 T1 xenograft mouse models. The innovative multi-compartment aggregates are able to fulfill structure-related function transitions with the variation of microenvironment, which has potential to extremely enrich the design of sophisticated biological agents. Graphical abstract Unlabelled Image [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Jocic-type protocol for the construction of the pyrrolonaphthoxazepine (PNOX) core. • A variety of reaction conditions were investigated. • The novel route significantly improved overall yields to obtain PNOX-based compounds. • The novel route was extended to the preparation of 1,4-benzoxazinone templates. Abstract We developed a Jocic-type protocol for the construction of the pyrrolonaphthoxazepine (PNOX) core. After an initial investigation based on the isolation of a trichloromethyl carbinol derivative, we shifted our attention towards a multicomponent single-step protocol. Screening of a variety of bases and solvents led to the identification of the optimum conditions for the preparation of the key α-aryloxy carboxylic acids to undergo intramolecular cyclization. The novel chemical route significantly improved overall yields for the preparation of PNOX-based compounds and was successfully extended to the preparation of 1,4-benzoxazinone-based templates. [ABSTRACT FROM AUTHOR]

A new ZnL 2 complex containing two molecules of a tridentate Schiff base derived from 5-methyl-1H-pyrazole (HL) is synthesized and characterized. The photophysical properties of HL and ZnL 2 are disclosed and supported by CAMB3LYP DFT/TDDFT calculations. It is shown that there is keto-tautomer stabilization upon excitation with an energetically accessible triplet state in HL, not present in ZnL 2 , this explaining the differences found in the emissions of the compounds. The intrinsic fluorescence of ZnL 2 is used as probe for a detailed study of its binding to human serum albumin. The protein-complex association is thermodynamically favourable and it is shown by fluorescence quenching and time-resolved analysis that the fluorescence quenching involves a mixed mechanism with prevalence of static quenching, which corroborates adduct formation at site I, close to the Trp214 residue. The ability of ZnL 2 to bind DNA was also evaluated, as well as its cytotoxic activity against MCF7 (breast), PC3 (prostate) cancer cells and hamster V79 fibroblasts. ZnL 2 is a moderate DNA intercalator (K app  = 3.9 × 10 4  M −1 ) and depicts a quite low IC 50 value at 48 h against MCF7 cells (IC 50  = 530 nM), but much higher for PC3 and V79 cells. The relevance of a more careful speciation evaluation of ZnL 2 and other potential metal-based drugs in incubation media used in in vitro tests is highlighted. [ABSTRACT FROM AUTHOR]

A series of 4-phenylamino-substituted naphthalene-1,2-dione derivatives were prepared and evaluated as effective antiproliferative agents. MTT assays showed that the compounds with a methyl group on the nitrogen linker exhibited potent antiproliferative activities against human cancer cells. The mechanistic study revealed that these compounds could induce mitochondrial depolarization, which resulted in intracellular ROS production, and they also acted as tubulin polymerization inhibitors. Moreover, the typical compound could arrest A549 cells in the G2/M phase, resulting in cellular apoptosis and induced mitotic arrest in A549 cells through disrupting microtubule dynamics. [ABSTRACT FROM AUTHOR]

Abstract This paper describes the rational development of a series of novel spiroindoline derivatives endowed with selective inhibitory activity on the HDAC6 isoform. A convenient multicomponent one-pot protocol was applied for the assembly of the desired N 1-substituted spiroindoline core which allowed a straightforward analoging. Computational studies and in vitro determination of inhibitory potency for the developed compounds against HDAC6 and HDAC1 isoforms were flanked by cell-based studies on histone H3 and α-tubulin acetylation. The effects on cancer cell cycle and apoptosis of the best performing derivatives were assessed on cancer cell lines highlighting a promising antitumor potential. In view of cell-based data and calculated drug-like properties, the selective HDAC6 inhibitor 5b , with a spiroindoline-based hydroxamate bearing a tert -butyl carbamate functionality, was selected to be further investigated for its potential in inhibiting tumor cells migration. It was able to potently inhibit cell migration in SH-SY5Y neuroblastoma cells and did not display toxicity in NIH3T3 mouse fibroblasts. Taken together, these data foster further investigation and optimization for this class of compounds as novel anticancer agents. Graphical abstract Image 1 Highlights • Rational design of novel spiroindoline as HDAC6 inhibitors. • Biological studies showed a strong antitumor potential for the synthesized compounds. • Compound 5b was able to potently inhibit cell migration in a SH-SY5Y cell culture. • Compound 5b did not display toxicity in NIH3T3 mouse fibroblasts. [ABSTRACT FROM AUTHOR]

The tumor vasculature with unique characteristics offers an attractive target for anti-cancer therapy. Herein, we put forward a novel antitumor therapeutic mechanism based on the gadofullerene nanocrystals (GFNCs), the agent we have previously shown to efficiently disrupt tumor vasculature by size-expansion with assistance of radiofrequency (RF). However, the tumor vascular disrupting mechanism of RF-assisted GFNCs treatment was not further studied. In the present work, a rapid tumor blood flow shutdown has been observed by the vascular perfusion imaging in vivo and vascular damages were evident 6 h after the RF-assisted GFNCs treatment. Importantly, a significant down-expression of tumor vascular endothelial cadherin (VE-cadherin) treated by RF-assisted GFNCs was further investigated, which caused vascular collapse, blood flow shut-down and subsequent tumor hemorrhagic necrosis. These findings set forth a systematic mechanism on the superior anti-tumor efficiency by RF-assisted GFNCs treatment. [ABSTRACT FROM AUTHOR]

Background Pyridoquinazolinecarboxamides have been reported as RNA polymerase I inhibitors and represent a novel class of potential antitumor agents. BMH-21, was reported to intercalate with GC-rich rDNA, resulting in nucleolar stress as a primary mechanism of cytotoxicity. Methods The interaction of BMH-21 and analogues with DNA G-quadruplex structures was studied by NMR and molecular modelling. The cellular response was investigated in a panel of human tumor cell lines and protein expression was examined by Western Blot analysis. Results and conclusions We explored the ability of BMH-21 and its analogue 2 to bind to G-quadruplex present in the c-MYC promoter, by NMR and molecular modelling studies. We provide evidence that both compounds are not typical DNA intercalators but are effective binders of the tested G-quadruplex. The interaction with c-MYC G-quadruplex was reflected in down-regulation of c-Myc expression in human tumor cells. The inhibitory effect was almost complete in lymphoma cells SUDHL4 characterized by overexpression of c-Myc protein. This downregulation reflected an early and persistent modulation of cMyc mRNA. Given the relevance of c-MYC in regulation of ribosome biogenesis, it is conceivable that the inhibition of c-MYC contributes to the perturbation of nuclear functions and RNA polymerase I activity. Similar experiments with CX-5461, another RNA polymerase I transcription inhibitor, indicate the same behaviour in G-quadruplex stabilization. General significance Our results support the hypothesis that BMH-21 and analogue compounds share the same mechanism, i.e. G-quadruplex binding as a primary event of a cascade leading to inhibition of RNA polymerase I and apoptosis. [ABSTRACT FROM AUTHOR]

1-(1-Naphthyl)piperazine (1-NPZ) is a serotonergic derivative of quipazine acting both as antagonist and agonist of different serotonin receptors, with promising results for the management of skin cancer. In this work, we studied the effect of 1-NPZ on human MNT-1 melanoma cells by evaluating its effects on cell viability, ability to form colonies, cell cycle dynamics, reactive oxygen species (ROS) production and apoptosis. Treatment of MNT-1 cells with 1-NPZ for 24 h decreased cell viability and induced apoptosis in a dose-dependent manner. Activity against melanoma was confirmed with a different melanoma cell line, SK-MEL-28. Simultaneously, 1-NPZ affected cell cycle progression by mediating a S-phase delay. Higher levels of ROS were also detected in MNT-1 cells after treatment with 1-NPZ. Furthermore, 1-NPZ significantly increased the expression of cyclooxygenase-2 in MNT-1 cells. These findings suggest that 1-NPZ pretreatment is able to induce oxidative stress, and consequently apoptotic cell death in melanoma cells. In conclusion, this study demonstrates the cytotoxic and genotoxic potential of 1-NPZ against melanoma cells. [ABSTRACT FROM AUTHOR]

Within the research field of antitumor metal-based agents alternative to platinum drugs, gold(I/III) coordination complexes have always been in the forefront due mainly to the familiarity of medicinal chemists with gold compounds, whose application in medicine goes back in the ancient times, and to the rich chemistry shown by this metal. In the last decade, N-heterocyclic carbene ligands (NHC), a class of ligands that largely resembles the chemical properties of phosphines, became of interest for gold(I) medicinal applications, and since then, the research on NHC-gold(I/III) coordination complexes as potential antiproliferative agents boosted dramatically. Different classes of gold(I/III)-NHC complexes often showed an outstanding in vitro antiproliferative activity, however up to now very few in vivo data have been reported to corroborate the in vitro results. This review summarizes all achievements in the field of gold (I/III) complexes comprising NHC ligands proposed as potential antiproliferative agents in the period 2004–2016, and critically analyses biological data (mainly IC 50 values) in relation to the chemical structures of Au compounds. The state of art of the in vivo studies so far described is also reported. [ABSTRACT FROM AUTHOR]

Iron depletion has been confirmed as an efficient strategy for cancer treatment. In the current study, a series of 1,4,7-triazacyclononane derivatives HE-NO2A, HP-NO2A and NE2P2A, as well as the bifunctional chelators p -NO 2 -PhPr-NE3TA and p -NH 2 -PhPr-NE3TA were synthesized and evaluated as iron-depleting agents for the potential anti-cancer therapy against human hepatocellular carcinoma. The cytotoxicity of these chelators was measured using hepatocellular cancer cells and compared with the clinically available iron depletion agent DFO and the universal metal chelator DTPA. All these 1,4,7-triazacyclononane-based chelators exhibited much stronger antiproliferative activity than DFO and DTPA. Among them, chelators with phenylpropyl side chains, represented by p -NO 2 -PhPr-NE3TA and p -NH 2 -PhPr-NE3TA, displayed the highest antiproliferative activity against HepG2 cells. Hence, these compounds are attractive candidates for the advanced study as iron depletion agents for the potential anti-cancer therapy, and could be further in conjugation with a targeting moiety for the future development in targeted iron depletion therapy. [ABSTRACT FROM AUTHOR]

Coumarin derivatives are a peculiar class of inhibitors of the family of metalloenzymes carbonic anhydrases (CA, EC 4.2.1.1). Several coumarins display higher affinity and selectivity toward most relevant and druggable CA isoforms. By decorating the natural compound umbelliferone ( 1 ) we have identified a new series of coumarin-based compounds demonstrating high CA inhibitory effects with nanomolar affinity for hCA IX and hCA XII isoforms that were considered a target amenable to develop antitumor agents. The most active tested compounds proved to be potent inhibitors with K i values equal to that of the well-known inhibitor acetazolamide (AAZ), that lacks selectivity over ubiquitous hCA I and hCA II. As suggested by docking studies the coumarins, that are lacking of the canonical metal binding groups, do not interact with Zinc ion within the catalytic site as found for classical sulfonamide type inhibitors of CAs. Thus, the studied inhibitors might possess a non-classical inhibitory mode of action preventing the carbon dioxide to entry into catalytic cavity and its conversion into bicarbonate ion. Specifically, the most active inhibitor of hCA XII compound 18i ( K i value of 5.5 nM) and its supposed hydrolytic products could establish a web of H-bond interactions within the enzymatic cavity. [ABSTRACT FROM AUTHOR]

Since the antitumor activity of cisplatin was discovered in 1967 by Rosenberg, platinum-based anticancer drugs have played an important role in chemotherapy in clinic. Nevertheless, platinum anticancer drugs also have caused severe side effects and cross drug resistance which limited their applications. Therefore, a significant amount of efforts have been devoted to developing new platinum-based anticancer agents with equal or higher antitumor activity but lower toxicity. Until now, a large number of platinum-based complexes have been prepared and extensively investigated in vitro and in vivo . Among them, some platinum-based complexes revealing excellent anticancer activity showed the potential to be developed as novel type of anticancer agents. In this account, we present such platinum-based anticancer complexes which owning various types of ligands, such as, amine carrier ligands, leaving groups, reactive molecule, steric hindrance groups, non-covalently binding platinum (II) complexes, Platinum(IV) complexes and polynuclear platinum complexes. Overall, platinum-based anticancer complexes reported recently years upon modern structure are emphasized. [ABSTRACT FROM AUTHOR]

[Display omitted] The natural products neorautenol and shinpterocarpin and their structural analogs were investigated as novel anticancer agents. Twenty-four analogs, including analogs containing a polar chain and simplified analogs, were synthesized efficiently by a modified method from previous reports. The antitumor screening of synthesized compounds toward six cancer cell lines indicated that compounds 37 , 42 and 43 with a dialkylaminoethyl-type side chain exhibited more promising activity than neorautenol and shinpterocarpin against lung and colon cancer lines with a range of 4–9 μM. They showed selective toxicity in normal cells. [ABSTRACT FROM AUTHOR]

Unsatisfactory outcomes for relapsed/refractory lymphoma patients prompt continuing efforts to develop new therapeutic strategies. Our previous studies on pyrrole-based anti-lymphoma agents led us to synthesize a new series of twenty-six pyrrolo[3′,4':3,4]cyclohepta[1,2- d ] [1,2]oxazole derivatives and study their antiproliferative effects against a panel of four non-Hodgkin lymphoma cell lines. Several candidates showed significant anti-proliferative effects, with IC 50 's reaching the sub-micromolar range in at least one cell line, with compound 3z demonstrating sub-micromolar growth inhibitory effects towards the entire panel. The VL51 cell line was the most sensitive, with an IC 50 value of 0.10 μM for 3z. Our earlier studies had shown that tubulin was a prominent target of many of our oxazole derivatives. We therefore examined their effects on tubulin assembly and colchicine binding. While 3u and 3z did not appear to target tubulin, good activity was observed with 3d and 3p. Molecular docking and molecular dynamics simulations allowed us to rationalize the binding mode of the synthesized compounds toward tubulin. All ligands exhibited a better affinity for the colchicine site, confirming their specificity for this binding pocket. In particular, a better affinity and free energy of binding was observed for 3d and 3p. This result was confirmed by experimental data, indicating that, although both 3d and 3p significantly affected tubulin assembly, only 3d showed activity comparable to that of combretastatin A-4, while 3p was about 4-fold less active. Cell cycle analysis showed that compounds 3u and especially 3z induced a block in G2/M, a strong decrease in S phase even at low compound concentrations and apoptosis through the mitochondrial pathway. Thus, the mechanism of action of 3u and 3z remains to be elucidated. Very high selectivity toward cancer cells and low toxicity in human peripheral blood lymphocytes were observed, highlighting the good potential of these agents in cancer therapy and encouraging further exploration of this compound class to obtain new small molecules as effective lymphoma treatments. [Display omitted] • 3u and 3z showed IC 50 values at submicromolar level against different lymphoma cells. • 3u and 3z displayed very high selectivity toward cancer cells and low toxicity in PBLs. • 3u and 3z induced cell cycle arrest in G2/M. • 3u and 3z induced apoptosis through the mitochondrial pathway. [ABSTRACT FROM AUTHOR]

Enzyme prodrug therapies hold potential as a targeted treatment option for cancer patients. However, off-target effects can be detrimental to patient health and represent a safety concern. This concern can be alleviated by including a failsafe mechanism that can abort the therapy in healthy cells. This feature can be included in enzyme prodrug therapies by use of conditional degradation tags, which degrade the protein unless stabilized. We call this process Degradation-Directed Enzyme Prodrug Therapy (DDEPT). Herein, we use traceless shielding (TShld), a mechanism that degrades a protein of interest unless it is rescued by the addition of rapamycin, to test this concept. We demonstrated that TShld rapidly yielded only native protein products within 1 h after rapamycin addition. The rapid protection phenotype of TShld was further adapted to rescue yeast cytosine deaminase, a prodrug converting enzyme. As expected, cell viability was adversely affected only in the presence of both 5-fluorocytosine (5-FC) and rapamycin. We believe that the DDEPT system can be easily combined with other targeting strategies to further increase the safety of prodrug therapies. [ABSTRACT FROM AUTHOR]

A series of mixed ligand complexes were prepared from the Schiff base (L 1 ) as a primary ligand, prepared by condensation of oxamide and furan-2-carbaldehyde, and 1,10-phenanthroline (1,10-phen) as a secondary ligand. The Schiff base ligand and its mixed ligand chelates were characterized based on elemental analysis, IR, 1 H NMR, thermal analysis, UV–Visible, mass, molar conductance, magnetic moment. X-ray diffraction, solid reflectance and ESR also have been studied. The mixed ligand complexes were found to have the formulae of [M(L 1 ) (1,10-phen)]Cl m .nH 2 O (M = Cr(III) and Fe(III) (m = 3) (n = 0); M = Mn(II), Cu(II) and Cd(II) (m = 2) (n = 0); and M = Co(II) (m = 2) (n = 1), Ni(II) (m = 2) (n = 2) and Zn(II) (m = 2) (n = 3)) and that the geometrical structure of the complexes were octahedral. The parameters of thermodynamic using Coats–Redfern and Horowitz–Metzger equations were calculated. The synthesized Schiff base ligand, 1,10-phenanthroline ligand and Their mixed ligand complexes were also investigated for their antibacterial and antifungal activity against bacterial species (Gram−Ve bacteria: Pseudomonas aeruginosa and Escherichia coli ) and (Gram + Ve bacteria: Bacillus subtilis and Streptococcus pneumonia ) and fungi ( Aspergillus fumigates and Candida albicans ). The anticancer activity of the new compounds had been tested against breast (MFC7) and colon (HCT-116) cell lines. The results showed high activity for the synthesized compounds. [ABSTRACT FROM AUTHOR]

In Latin America Chagas disease is an endemic illness caused by the parasite Trypanosoma cruzi (T. cruzi) , killing more people than any other parasitic disease. Current chemotherapies are old and inadequate, thus the development of efficient ones is urgently needed. Vanadium-based complexes have been shown to be a promising approach both against parasitic diseases and cancer and this study aims to achieve significant advances in the pursue of effective compounds. Heteroleptic vanadium complexes of Schiff bases and polypyridine compounds were prepared and their stability in solution evaluated by EPR (Electronic Paramagnetic Resonance) and NMR spectroscopy. Their in vitro activities were evaluated against T . cruzi and a set of cell s lines representative of human cancer conditions, namely ovarian, breast and prostate cancer. In T . cruzi , most of the complexes depicted IC 50 values in the low μM range, induced changes of mitochondrial membrane potential and apoptosis. In cancer cells, complexes showed good to moderate activity and in metastatic cells (prostate PC3), some complexes inhibited the migratory ability, this suggesting that they display antimetastatic potential. Interestingly, complex 5 seemed to have a dual effect being the most cytotoxic complex on all cancer cells and also the most active anti- T - cruzi compound of the series. Globally the complexes showed promising anticancer and anti T . cruzi activities and also displayed some characteristics indicating they are worth to be further explored as antimetastatic drugs. [ABSTRACT FROM AUTHOR]

The search for antimetastatic agents for cancer therapy may involve the ability of new compounds to maintain the tissue extracellular matrix integrity. Among known factors, heparanase, an endoglucuronidase responsible for heparan sulfate cleavage, is a promising target whose inhibition could represent a strong obstacle for metastatic cancerous mechanisms. The antimetastatic activity of some suramin derivatives reported in literature suggests a possible involvement of the heparanase enzyme. To confirm such hypothesis, we have investigated FCE27266, a molecule known for its antiangiogenic and antimetastatic properties. Other new derivatives were also synthesized and investigated. Our findings revealed that FCE27266 as well as some derivatives have a strong heparanase inhibition activity, together with no cytotoxic power. Moreover, a FCE27266 analogue (SST0546NA1; 17a ) resulted also positive to lower gene expression of some proangiogenic factors. [ABSTRACT FROM AUTHOR]

New Pt(II) complexes (Pt-1-3) bearing 1,2,5-oxadiazole ligands (1-3) were synthesized, characterized and evaluated for their ability to disrupt STAT3 dimerization. Ligand 3·HCl showed cytotoxic effects on HCT-116 cells (IC50 = 95.2 μM) and a selective ability to interact with STAT3 (IC50 = 8.2 μM) versus STAT1 (IC50 > 30 μM). Its corresponding platinum complex Pt-3 exhibited an increased cytotoxicity (IC50 = 18.4 μM) and a stronger interaction with STAT3 (IC50 = 1.4 μM), leading to inhibition of its signaling pathway. Pt-3 was also evaluated in cell-based assays for its action on p53 expression and on STAT3 phosphorylation. In syngeneic murine Lewis lung carcinoma (LLC) implanted in C57BL/6 mice, Pt-3 showed a higher antitumor activity with fewer side effects than cisplatin. [ABSTRACT FROM AUTHOR]

Novel bis(hydroxymethyl) alkanoate curcuminoid derivatives were designed, synthesized and screened for in vitro antiproliferative and in vivo antitumor activity. Selected new compound 9a and curcumin were further evaluated for inhibitory activity against ER+/PR+ breast cancer (MCF-7, T47D), HER 2+ breast cancer (SKBR3, BT474, and MDA-MB-457) and triple negative breast cancer (TNBC) (HS-578T, MDA-MB-157, and MDA-MB-468) cell lines. In addition, compound 9a was evaluated in the MDA-MB-231 xenograft nude mice model. Compound 9a exhibited greater inhibitory activity than curcumin against TNBC cells and also demonstrated significant inhibitory activity against doxorubicin-resistant MDA-MB-231 cells, with ten-fold higher potency than curcumin. Furthermore, when evaluated against the MDA-MB-231 xenograft nude mice model, compound 9a alone was ten-fold more potent than curcumin. Moreover, synergistic activity was observed when 9a was used in combination with doxorubicin against MDA-MB-231 breast cancer cells. [ABSTRACT FROM AUTHOR]

Nucleoside analogues are among the most known drugs commonly used in antiviral and anticancer chemotherapies. Among them, those featuring a five-membered ring nucleobase are of utmost interest such as the anti-cancer agent AICAR or the anti-viral drug ribavirin. Despite its low activity in vitro in different cell lines, AICAR is under clinical development for several pathologies, thanks to its original mode of action. Indeed, AICAR induced autophagy cell death and is able, following this mechanism, to circumvent resistance to apoptotic drugs including kinase inhibitors currently on the market. To improve the activity of AICAR, we report herein an efficient synthesis of new series of sulfonamide-4-substituted-1,2,3-triazolyl nucleosides using a Cu-catalyzed 1,3-dipolar cycloaddition. All these molecules have been fully characterized and evaluated against two aggressive tumor cell lines, RCC4 and MDA-MB-231. Among them, nucleoside analogue 5i belonging to the ribose series was found to be 19 to 66-fold more active than AICAR. Western blot analyses on RCC4 cells showed that 5i displayed an interesting mode of action by inducing both apoptosis and autophagy cell death, making therefore this class of molecules highly promising for further hit-to-lead optimization. [ABSTRACT FROM AUTHOR]

DNA intercalating agents are a consolidated therapeutic option in the treatment of tumor diseases. Starting from previous findings in the antiproliferative efficacy of a series of indeno[1,2- c ]cinnoline-11-one derivatives, we performed a suitable decoration of this scaffold by means of a simple and straightforward chemistry, aiming to a) enlarge the planar core to a pentacyclic benzo[ h ]indeno[1,2- c ]cinnoline-13-one and b) introduce a basic head tethered through a simple polymethylene chain. In fluorescence melting and fluorescence intercalator displacement assays, these new compounds displayed fair to very good intercalating properties on different nucleic acid strands, with preference for G-quadruplex sequences. Inhibition of human topoisomerase IIα and antiproliferative assays on HeLa and MCF7 tumor cell lines outlined a multitarget antiproliferative profile for tetracyclic 6 and pentacyclic derivative 20 , both bearing a N , N -dimethylamine as the protonatable moiety. Particularly, compound 6 displayed a very potent inhibition of tumor cell proliferation, while 20 returned the highest thermal stabilization in melting experiments. In summary, these results outlined a potential of such highly planar scaffolds for nucleic acid binding and antiproliferative effects. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate nine newly synthesized amidine derivatives of 3,4- ethylenedioxythiophene (3,4-EDOT) for their cytotoxic activity against a panel of human cancer cell lines and to perform a quantitative structure–activity relationship (QSAR) analysis for the antitumor activity of a total of 27 3,4-ethylenedioxythiophene derivatives. Induction of apoptosis was investigated on the selected compounds, along with delivery options for the optimization of activity. The best obtained QSAR models include the following group of descriptors: BCUT, WHIM, 2D autocorrelations, 3D-MoRSE, GETAWAY descriptors, 2D frequency fingerprint and information indices. Obtained QSAR models should be relieved in elucidation of important physicochemical and structural requirements for this biological activity. Highly potent molecules have a symmetrical arrangement of substituents along the x axis, high frequency of distance between N and O atoms at topological distance 9, as well as between C and N atoms at topological distance 10, and more C atoms located at topological distances 6 and 3. Based on the conclusion given in the QSAR analysis, a new compound with possible great activity was proposed. [ABSTRACT FROM AUTHOR]

The triphenyltin(IV) compound with N - tert -butoxycarbonyl- l -ornithine (Boc-Orn-OH), [Ph 3 Sn(Boc-Orn-O)], was synthesized and characterized by elemental analysis, FT-IR, solution 1 H, 13 C and 119 Sn NMR and ESI mass spectrometry. The organotin(IV) compound inhibited at very low micromolar concentrations the growth of human tumor cell lines HepG2 (hepatocarcinoma cells), MCF-7 (mammary cancer) and HCT116 (colorectal carcinoma) while it did not affect the viability of non-malignant human-derived hepatic cells Chang. The mechanism of the antiproliferative effect of Ph 3 Sn(Boc-Orn-O), investigated on human hepatoma HepG2 cells, was pro-apoptotic, being associated with externalization of plasma membrane phosphatidylserine, chromatin condensation or fragmentation and mitochondrial dysfunction as well as with increase of p53 levels. [ABSTRACT FROM AUTHOR]

STAT3 is an attractive therapeutic target for cancer therapy. However, due to low potency or poor druggability, none of its inhibitors are clinically available. Herein, a series of aminobenzo[ b ]thiophene 1, 1-dioxides with good drug-likeness properties were designed, synthesized and evaluated as STAT3 inhibitors. Most of them exhibited higher antitumor activity than the small-molecule STAT3 inhibitor, Stattic. Compound 15 was the most potent and had an IC 50 range in 0.33–0.75 μM in various cancer cell lines. The overexpressed and IL-6 induced phosphorylation levels of STAT3 were both inhibited by 15 without influencing the phosphorylation levels of the upstream kinases Src and Jak2. 15 also suppressed the expressions of STAT3 downstream gene, Bcl-2. 15 effectively increased the ROS levels of cancer cells, induced cancer cell apoptosis and abolished the colony formation ability of cancer cells without affecting bypass kinase p-Erk. Furthermore, 15 in vivo induced significant antitumor responses, and exhibited less toxicity than Doxorubicin. Together, this study described a class of new STAT3 inhibitors as antitumor agents. [ABSTRACT FROM AUTHOR]

• Compounds 15a-k were synthesized as antitumoral agents. • 15c, 15e , 15g, and 15k showed significant cytotoxicity. • 15c, g , and k increased the levels of reactive species and superoxide ions. • In silico toxicity screening showed that 15g presented low hepatotoxicity risk. • 15g is a potential candidate to optimize for the development of anticancer agents. Breast cancer is the leading cause of cancer death in women. Although the available treatments are efficient, cancer cells promptly develop resistance to different drugs, leading to disease relapse and promoting tumor progression. Here, novel 4-oxoquinoline-3-carboxamide acyclonucleoside phosphonate hybrids were synthesized as antitumoral agents, and in silico toxicity screening were performed. Derivatives 15c, 15e , 15g, and 15k showed significant cytotoxicity where 15c induces the most considerable loss of cell viability through the apoptotic process, while 15k induces cell death by necrosis. All compounds, except 15e , induced the production of OH- and NO, besides increasing the levels of superoxide ions. In silico toxicity studies showed that 15g presented low hepatotoxicity risk and probability as BCRP substrate. These findings point out that derivative 15g is a potential candidate for an optimization program for the development of new anticancer agents. [Display omitted] [ABSTRACT FROM AUTHOR]

Studies on the immobilization of oxindolimine‑copper(II) or zinc(II) complexes [ML] in synthetic beidellite (BDL) clay were developed to obtain a suitable inorganic carrier capable of promoting the modified-release of metallopharmaceuticals. Previous investigations have shown that the studied metal complexes are promising antitumor agents, targeting DNA, mitochondria, and some proteins. They can bind to DNA, causing oxidative damage via formation of reactive oxygen species (ROS). In mitochondria they lead to a decrease in membrane potential, acting as decoupling agents, and therefore efficiently inducing apoptosis. Additionally, they inhibit human topoisomerase IB and cyclin dependent kinases, proteins involved in the cell cycle. BDL clays in the sodium form were synthesized under hydrothermal conditions and characterized by a set of physicochemical techniques while the BDL-[ML] hybrid materials were prepared by ion exchange method. The characterization of pristine clay and the obtained hybrids were performed by Infrared, Raman, electron paramagnetic resonance and energy dispersive X-ray spectroscopies, thermogravimetric analysis, scanning electron microscopy, X-ray powder diffraction, specific surface area, zeta potential and surface ionic charge measurements. The [ML] release assays under the same cell incubation conditions were performed monitoring metals by X-ray fluorescence. The BDL-[CuL] hybrid materials were stable and able to derail tumor HeLa cells, with corresponding IC 50 values in the 0.11–0.41 mg mL−1 range. By contrast, the analogous hybrid samples of zinc(II) and the pristine BDL proved to be non-toxic facing the same cells. These results indicate a promising possibility of using synthetic beidellite as a carrier of such antitumor metal complexes. Immobilization of oxindolimine-copper(II) or zinc(II) complexes in synthetic beidellite (BDL) clay was provided to obtain a suitable inorganic carrier capable of promoting the modified-release of antitumor metallopharmaceuticals. [Display omitted] • Oxindolimine-copper(II) or zinc(II) complexes were supported in beidellite clay. • Characterization of materials were performed by diverse spectroscopies. • Clay-[CuL] hybrid materials were stable and able to derail tumor HeLa cells. • Analogous Clay-[ZnL] hybrid samples and the pristine clay proved to be non-toxic. • [ML] release assays were performed monitoring copper or zinc by X-ray fluorescence. [ABSTRACT FROM AUTHOR]

The four novel complexes [{ cis -PtCl(NH 3) 2 (μ -4,4′-bipyridyl)ZnCl(terpy)}](ClO 4) 2 (C1), [{ trans -PtCl(NH 3) 2 (μ -4,4′-bipyridyl)ZnCl(terpy)}](ClO 4) 2 (C2), [{ cis -PtCl(NH 3) 2 (μ -pyrazine)ZnCl(terpy)}](ClO 4) 2 (C3) and [{ trans -PtCl(NH 3) 2 (μ -pyrazine)ZnCl(terpy)}](ClO 4) 2 (C4) (where terpy = 2,2′:6′,2′′-terpyridine) were synthesized and characterized. Acid–base titrations and concentration dependent kinetic measurements for the reactions with biologically relevant ligands such as guanosine-5′-monophosphate (5′-GMP), inosine-5′-monophosphate (5′-IMP) and glutathione (GSH), were studied at pH 7.4 and 37 °C. The binding of the heterometallic bridged cis- or trans- Pt(II)-Zn(II) complexes to calf thymus DNA (CT-DNA) was studied by UV absorption and fluorescence emission spectroscopy and molecular docking. The results indicated that the complexes bind strongly to DNA, through groove binding, hydrogen bonds, and hydrophobic or electrostatic interaction. The possible in vitro DNA protective effect of cis - and trans -Pt-L-Zn complexes has shown that C3 had significant dose-dependent DNA-protective effect and the same ability to inhibit peroxyl as well as hydroxyl radicals. Antiproliferative effect of the complexes, mRNA expression of apoptosis and repair-related genes after treatment in cancer cells indicated that newly synthesized C2 exhibited highly selective cytotoxicity toward colon carcinoma HCT116 cells. Only treatment with trans analog C2 induced effect similar to the typical DNA damaging agent such as cisplatin, characterized by p53 mediated cell response, cell cycle arrest and certain induction of apoptotic related genes. Both cis - and trans - isomers C1 and C2 showed potency to elicit expression of PARP1 mRNA and in vitro DNA binding. The four novel heterometallic bridged Pt(II)-Zn(II) complexes were synthesized, characterized and evaluated for antitumor activity. The isomers cis - and [{ trans -PtCl(NH 3)(μ -4,4′-bipyridyl)ZnCl(terpy)}](ClO 4) 2 were showed potential to elicit expression of PARP1 mRNA and in vitro DNA binding with highly selective cytotoxicity toward colon carcinoma HCT116 cells. [Display omitted] • The four novel heterometallic bridged cis- or trans- Pt(II)-L-Zn(II) complexes. • Strongly binding to DNA through groove binding • Significant dose-dependent DNA-protective effect and the same ability to inhibit peroxyl radical. • Highly selective cytotoxicity toward colon carcinoma HCT116 cells. [ABSTRACT FROM AUTHOR]

Mitochondria has been identified as a target for tumor therapy. Agents preferentially concentrated in mitochondria may exert more potent antitumor effects by interfering with the normal function of mitochondria. Glutathione reductase (GR) in mitochondria is a crucial antioxidant enzyme to maintain mitochondrial function, and has been recognized as an important target for the development of anticancer drugs. Herein, we present a triphenylphosphonium-modified anticancer agent, MT-1 , which can preferentially accumulate in mitochondria and bind to GR by covalent binding manner. As a result, morphology and function of mitochondria were severely damaged, as well as cellular energy supply was severely impeded due to the simultaneously inhibition against mitochondrial respiration and glycolysis. Moreover, MT-1 was found to bind to a completely new site of GR (C278) that has never considered as binding site of inhibitors before. This new binding mode led to the change of GR structure, which affected the stability of the transition state of the catalytic process, and finally led to the inhibition of GR activity. Thus, current study provided a potentially novel tumor therapeutic strategy by targeting novel sites of GR in mitochondrion. [Display omitted] • Mitochondrial targeting strategy was used in enhancing the antitumor activity. • MT-1 damaged morphology and function of mitochondria. • MT-1 simultaneously inhibited mitochondrial respiration and glycolysis. • A novel drug binding site was identified in glutathione reductase (GR). [ABSTRACT FROM AUTHOR]

[Display omitted] Four mononuclear n,π-chelate complexes [ M (HL1,2)Cl 2 ] (M = Pd2+, Pt2+) have been obtained by the reactions of PdCl 2 or K 2 [PtCl 4 ] with N , N -diethyl- N' -(2-propenyl)thiourea (HL1) or N -cyclohexyl- N' -(2-propenyl)thiourea (HL2) in the presence of HCl. According to X-ray diffraction study, the molecules of HL1,2 are coordinated in a bidentate manner with the formation of six-membered chelate metallocycles in a twist-boat conformation. The diagonal arrangement of "soft-hard" donor atoms (S–M−Cl, C–M−Cl) in the coordination sphere leads to the Pearson's effect of "molecular antisymbiosis in the trans effect" that causes the formation of complexes with an M:L ratio of 1:1. However, interaction in the ratio 1:2, 1:3 is also possible in the solution under the conditions of monodentate coordination of HL1 and HL2. All compounds were investigated by IR, UV–vis and NMR spectra. The 1H/13C NMR study showed that this method is reliable for establishing the formation of a π-coordinating bond. The similarity of the synthesized complexes structure with cisplatin implies the same mechanism of their antitumor action. Thus, it was investigated their effect on the growth and biochemical characteristics of human breast adenocarcinoma cells MCF-7 (grown in three-dimensional culture as spheroids) and the activity of the enzyme gamma-glutamyl transpeptidase (GGT). The results showed that all studied π-complexes are more active compared to cisplatin, and they exhibit pronounced anti -metastatic and pro -apoptotic activity, which one is caused by their inhibitory effect. [ABSTRACT FROM AUTHOR]

A mononuclear compound of the general formula [(η 6 - p -cymene)Ru II Cl(2,2′-PyBIm)]PF 6 has been synthesized from a bidentate N,N-donor ligand, viz . 2,-(2′-pyridyl)benzimidazole (2,2′-PyBIm) and the corresponding chloro-complex [(η 6 - p -cymene)Ru(μ-Cl)Cl] 2 (precursor). The isolated coordination compound was characterized by IR, UV–vis and 1 H, 13 C NMR spectroscopies. The single crystal X-ray analysis of the complex reveals that the asymmetric part of the unit cell consists of two symmetrically independent, [(η 6 - p -cymene)RuCl(2,2′-PyBIm)] + cationic complexes. Each cation exhibits a pseudo-octahedral three-legged piano-stool geometry, in which three “legs” are occupied by one chloride ion and two nitrogen donor atoms of the chelating ligand 2,2′-PyBIm. The Hirshfeld surface analysis of obtained complex was determined, too. The ionic nature of the compound is identified by a strong band at around 830 cm −1 due to the ν P−F stretching mode of the PF 6 − counter ion. The electronic spectrum of this monomeric complex displays high intensity bands in the ultraviolet region assignable to π→π*/n→π* transitions, as well as a band attributable to the metal-to-ligand charge transfer (MLCT) dπ(Ru)→π*(L) transition. Additionally, the complex has been screened for its cytotoxicity against three human cancer lines: non-small cell lung carcinoma (A549), colon adenocarcinoma (HT29) and breast adenocarcinoma (MCF-7) as well as normal mice fibroblast cells (BALB/3T3). The complex demonstrated a moderate antiproliferative activity against the cell lines tested. [ABSTRACT FROM AUTHOR]

Ruthenium compounds have unique physicochemical properties that can be efficiently exploited in medicinal chemistry. These molecules can act using both DNA or enzymes as target. The molecular bases that govern DNA versus protein binding selectivity are not known, but a number of investigations has allowed one to obtain significant information on these recognition processes. Here we review some relevant crystallographic studies focused on the characterization of the interaction between proteins and selected ruthenium compounds of medicinal interest. Details of the interactions between Ru compounds and protein residues are described and the reactivity of the compounds towards different targets is compared with that observed analyzing analogous Pt-based drugs-protein adducts. Data provide important information that can be useful to a deeper understanding of the mechanism of actions of the analyzed compounds. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Three new 2,4-dinitrobenzenesulfonyl derivatives 1 – 3 were successfully prepared for the first time. • The inducible reactions of 1 – 3 were immediately triggered by RSH. • The inducible activity of 1 was highly selective for RSH over other amino acids. • Compound 1 could release of the corresponding phenol derivative and induce DNA cross-linking. Abstract Three new 2,4-dinitrobenzenesulfonyl derivatives 1 – 3 were successfully prepared for the first time using a simple process. They were efficiently triggered by thiols (glutathione and l -cysteine) to release the corresponding phenol derivatives (4 – 6) within 5 min. The quick response of 1 – 3 toward thiols was determined by 1H NMR and HPLC. Moreover, our results indicated that 1 could induce DNA cross-linking in the presence of glutathione, probably due to the quinone methide formation of phenol intermediate 4 followed by departure of 2,4-dinitrobenzenesulfonyl group. [ABSTRACT FROM AUTHOR]

In the search for new cytotoxic drugs, two copper complexes with isomeric dipeptides (Ala-Phe and Phe-Ala) were developed in order to determine the influence of their different structures in the modulation of the chemical, biochemical and biological properties. Spectroscopic, voltammetric and equilibrium studies were performed providing information about the chemical properties. The superoxide dismutase (SOD) activity was studied and showed differences of IC 50 for both Cu-Ala-Phe (IC 50 = 4.5) and Cu-Phe-Ala (IC 50 = 45). The computational results permitted to explain this behavior proposing that it is feasible that the O 2 − anion is attracted straight to the positive zone in Cu-Ala-Phe whereas for Cu-Phe-Ala this phenomenon would happen to a smaller extent. Confirming our previous studies, both complexes interacted with DNA. Molecular docking studies showed that the position of the phenyl ring modulates the complex-DNA affinity and in Cu-Ala-Phe the docked conformation allows the copper ion to face the DNA basis, giving rise to a more stable complex-DNA adduct than for Cu-Phe-Ala. In spite of the fact that Atomic Force Microscopy showed plasmid compactation and aggregation for both complexes, the image showed softer changes in the case of Cu-Ala-Phe in comparison with those produced by Cu-Phe-Ala. In order to evaluate the effect of Cu-Ala-Phe and Cu-Phe-Ala complexes against tumor cells, we have employed three aggressive metastatic breast adenocarcinoma cellular models, derived from human (MDA-MB-231 and MCF-7) and mouse (4T1) spontaneous tumors. These experiments showed that both Cu-dipeptide complexes have a similar cytotoxic effect against breast cancer cells, and lower toxicity against BJ non-tumor cells in comparison to Cisplatin. [ABSTRACT FROM AUTHOR]