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Cytotoxic payloads for drug conjugates suitable for directed tumor therapy need to be highly potent and require a functional group for conjugation with the homing device (antibody, peptide, or small molecule). Cryptophycins are cyclodepsipeptides that stand out from the realm of natural products due to their extraordinarily high cytotoxicity. However, the installation of a suitable conjugation handle without compromising the toxicity is highly challenging. The unit D, natively 2‐hydroxyisocaproic acid (leucic acid), was envisaged as a promising attachment site based on structural information from X‐ray analysis. A versatile, scalable and efficient synthetic route towards conjugable cryptophycins with modification in unit D was developed and an array of new cryptophycin analogues was synthesized. Several derivatives, especially those containing lipophilic groups with low steric demand such as alkylated amino groups, exhibit low picomolar cytotoxicity often combined with efficacy against multidrug‐resistant tumor cells. The newly established cryptophycin analogues comprise a broad range of relevant functional groups used as conjugation handles, among them amino, hydroxy, carboxy, as well as sulfur‐containing derivatives. X‐ray crystallographic analysis of a tubulin‐bound cryptophycin together with quantitative structure activity relationship manifested rationales for the synthesis of most potent cryptophycin derivatives and further confirmed the suitability of modifications in unit D. [ABSTRACT FROM AUTHOR]

In this work, we report the identification of novel bromodomain‐containing protein 9 (BRD9) binders through a virtual screening based on our developed 3D structure‐based pharmacophore model. The in silico workflow here described led to the identification of a promising initial hit (1) featuring the 1‐ethyl‐1H‐pyrazolo[3,4‐b]pyridine motif which represented an unexplored chemotype for the development of a new class of BRD9 ligands. The encouraging biophysical results achieved for compound 1 prompted us to explore further tailored structural modification around the C‐4 and C‐6 positions of the central core. Hence, the design and synthesis of a set of 19 derivatives (2–20) were performed to extensively investigate the chemical space of BRD9 binding site. Among them, four compounds (5, 11, 12, and 19) stood out in biophysical assays as new valuable BRD9 ligands featuring IC50 values in the low‐micromolar range. Noteworthy, a promising antiproliferative activity was detected in vitro for compound 5 on HeLa and A375 cancer cell line. The successful combination and application of in silico tools, chemical synthesis, and biological assays allowed to identify novel BRD9 binders and to expand the arsenal of promising chemical entities amenable to the recognition of this important epigenetic target. [ABSTRACT FROM AUTHOR]

Air‐stable cyclometalated palladium(II) complexes with benzamide ligands were synthesized in high yields and characterized by X‐ray diffraction analysis, CVA, 1H NMR, 13C NMR spectroscopy, MALDI‐MS, and ESI‐MS. The electrochemical oxidation of the complexes is reversible in the presence of a quinoline substituent in the ligand and gives Pd (III) species that do not undergo reductive elimination and are detectable by ESR spectroscopy. The complexes showed high cytotoxicity against cervical cancer (M‐HeLa) and duodenal adenocarcinoma (HuTu 80), a human mammary ductal adenocarcinoma line (MCF‐7) and a human lung carcinoma cell line (A549). The possibility of generating reactive oxygen species in solution (such as OH−radicals), which can be responsible for the antitumor activity of the studied complexes, using the ESR method was shown. [ABSTRACT FROM AUTHOR]

We conducted an in‐depth exploration of the in vitro activities of the dinuclear Mn2L2Ac and Mn2L2 complexes (where HL=2‐{[di(2‐pyridyl)methylamino]‐methyl}phenol), possessing dual superoxide dismutase (SOD) and catalase (CAT) activity. We investigated these complexes both individually and in conjunction with various Pt(II)‐complexes, either as mixtures or as the Mn2‐Pt adducts. Our findings revealed a notable up to 50 % enhancement in the viability of healthy human breast cells, contrasted with a viability decrease as low as 50 % in breast cancer cells upon combined treatments with Mn2 SOD mimics and Pt(II) complexes. Specifically, we synthesized and characterized the self‐assembled Mn2‐Pt adducts (isolated Mn2L2Pt and in situMn2L2Pt'), linking Mn2L2‐core with the carboxylate group of PtDAPCl2 (dichloro(2,3‐diaminopropionic acid) platinum(II)). The SOD activity of the isolated Mn2L2Pt adduct (kSOD=1.7×107 M−1 s−1) remained intact. Through in vitro cell viability assessments, ROS levels, cellular Mn uptake and proteomics measurements, we elucidated key mechanisms underlying the observed biological effects. We demonstrated that Mn2‐containing formulations predominantly target mitochondrial processes, differently affecting the proteome of cancerous and healthy cells. They induced downregulation of H2S signaling and expression of mitochondrial complex I and III, as well as increased oxidative phosphorylation pathways and upregulation of EGFR in cancer cells. In contrast, healthy cells showed a decrease in EGFR expression and a moderate enrichment in oxidative phosphorylation pathways. [ABSTRACT FROM AUTHOR]

BOIMPY (bis‐ (borondifluoride)‐8‐imidazodipyrromethene) photosensitizers were developed for imaging‐guided photodynamic therapy (PDT). The introduction of heavy atoms (Br and I) to the β‐positions of BOIMPY combined with the twisted structure of the molecule was the strategy to enhance the intersystem crossing process of the BOIMPYs and reduce intermolecular π–π interactions of BOIMPY core. To clarify the electronic features of BOIMPY derivatives, their optical properties were studied using UV‐vis absorption, fluorescence spectroscopy, electrochemistry, and density functional theory (DFT) computing. The halogenated BOIMPYs exhibited a high absorption coefficient with high singlet oxygen generation ability (ΦΔ=0.46 and 0.94 for brominated and iodinated BOIMPY, respectively). More significantly, an in vitro investigation showed that all derivatives displayed fluorescence in cancer cells and that the halogenated BOIMPYs increased the effectiveness of tumor inhibition upon exposure to 660 nm red LED light radiation. The half‐maximal inhibitory concentrations for the iodinated and brominated BOIMPYs were 2.14 μM and 14.78 μM, respectively. Consequently, iodinated BOIMPY has been shown to represent a new class of photosensitizers with potential use in imaging‐guided photodynamic therapy. [ABSTRACT FROM AUTHOR]

Abstract Precise and effective initiation of the apoptotic mechanism in tumor cells is one of the most promising approaches for the treatment of solid tumors. However, current techniques such as high-temperature ablation or gene editing suffer from the risk of damage to adjacent normal tissues. This study proposes a magnetothermal-induced CRISPR-Cas9 gene editing system for the targeted knockout of HSP70 and BCL2 genes, thereby enhancing tumor cell apoptosis. The magnetothermal nanoparticulate platform is composed of superparamagnetic ZnCoFe2O4@ZnMnFe2O4 nanoparticles and the modified polyethyleneimine (PEI) and hyaluronic acid (HA) on the surface, on which plasmid DNA can be effectively loaded. Under the induction of a controllable alternating magnetic field, the mild magnetothermal effect (42℃) not only triggers dual-genome editing to disrupt the apoptosis resistance mechanism of tumor cells but also sensitizes tumor cells to apoptosis through the heat effect itself, achieving a synergistic therapeutic effect. This strategy can precisely regulate the activation of the CRISPR-Cas9 system for tumor cell apoptosis without inducing significant damage to healthy tissues, thus providing a new avenue for cancer treatment.

Photodynamic therapy (PDT) can destroy tumor cells by generating singlet oxygen (1O2) under light irradiation, which is limited by the hypoxia of the neoplastic tissue. Chemodynamic therapy (CDT) can produce toxic hydroxyl radical (⋅OH) to eradicate tumor cells by catalytic decomposition of endogenous hydrogen peroxide (H2O2), the therapeutic effect of which is highly dependent on the concentration of H2O2. Herein, we propose a BODIPY‐ferrocene conjugate with a balanced 1O2 and ⋅OH generation capacity, which can serve as a high‐efficiency antitumor agent by combining PDT and CDT. The ferrocene moieties endow the as‐prepared conjugates with the ability of chemodynamic killing of tumor cells. Moreover, combined PDT/CDT therapy with improved antitumor efficiency can be realized after exposure to light irradiation. Compared with the monotherapy by PDT or CDT, the BODIPY‐ferrocene conjugates can significantly increase the intracellular ROS levels of the tumor cells after light irradiation, thereby inducing the tumor cell apoptosis at low drug doses. In this way, a synergistic antitumor treatment is achieved by the combination of PDT and CDT. [ABSTRACT FROM AUTHOR]

Irisquinone is a tumor radiotherapy sensitizer and has been found to have broad-spectrum antitumor activity in recent years. The current acquisition method of extracting and purifying from semen irisis has greatly limited its wide application and activity study deeply. In this work an efficient route for the synthesis of the irisquinone was investigated to solve the source of it. The target compound was synthesized by 5-step reactions to Wittig reaction, reduction, oxidation, Wittig reaction, and oxidation using 3,5-dimethoxycarboxaldehyde as the starting material with an overall yield of 48%. The key factors such as the ratio of raw materials, temperatures, solvents, reaction times, and types of base for the main reactions were optimized. In addition, the deprotection and reduction were completed with Pd/C catalytic simultaneously when compound 2 was synthesized from compound 1. In the last reaction, the 3,5-dimethoxybenzene moiety of compound 4 was directly oxidized to 6-methoxy-1,4-benzoquinone by K3 [Fe(CN)6 ]/H2 O2 without the need to selectively remove the methyl protecting group, which were the innovative points in the experimental route design of the irisquinone synthesis. This work has opened new perspectives for the artificial synthesis and the development of irisquinone. [ABSTRACT FROM AUTHOR]

Herein, we describe the synthesis of pH-sensitive lipophilic colchicine prodrugs for liposomal bilayer inclusion, as well as preparation and characterization of presumably stealth PEGylated liposomes with above-mentioned prodrugs. These formulations liberate strongly cytotoxic colchicinoid derivatives selectively under slightly acidic tumor-associated conditions, ensuring tumor-targeted delivery of the compounds. The design of the prodrugs is addressed to pH-triggered release of active compounds in the slight acidic media, that corresponds to tumor microenvironment, while keeping sufficient stability of the whole formulation at physiological pH. Correlations between the structure of the conjugates, their hydrolytic stability, colloidal stability, ability of the prodrug retention in the lipid bilayer are described. Several formulations were found promising for further development and in vivo investigations. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: Hierarchically porous materials (HP materials) are believed one of the most hopeful matrix materials because of their distinctive multimodal pore structures and tremendous application potentials in the field of biomedicine. However, green and facile synthesis of hierarchically porous nanomaterials with beneficial water dispersibility and biocompatibility is still a great challenge. Herein, a novel biomimetic strategy is proposed to prepare the cell‐tailored double‐shelled HPCaCO3/CaF2 hollow nanospheres under the mediation of yeast cells. The biomolecules derived from the secretion of yeast cells are used as conditioning and stabilizing agents to control the biosynthesis of the HPCaCO3/CaF2 materials, which exhibit excellent water dispersibility and favorable biocompatibility. The double‐shelled CaCO3/CaF2 nanospheres hold hierarchically porous structure and have abundant pore channel and large specific surface area, showing high drug‐loading and a prolonged drug sustainable release profile by the pore‐by‐pore diffusion pattern of the hierarchical pores. Otherwise, the HPCaCO3 with pH‐sensitivity could controllably release drug doxorubicin hydrochloride (DOX) at the acidic tumor microenvironment. Both in vitro and in vivo results demonstrate that HPCaCO3/CaF2 has the sustainable pH‐sensitive drug release property, showing an enhanced therapeutic effect. Summarily, this study provides a biomimetic strategy to synthesize the hierarchically porous double‐shelled hollow nanomaterials for applying in sustainable drug delivery system. [ABSTRACT FROM AUTHOR]

Precise and effective initiation of the apoptotic mechanism in tumor cells is one of the most promising approaches for the treatment of solid tumors. However, current techniques such as high-temperature ablation or gene editing suffer from the risk of damage to adjacent normal tissues. This study proposes a magnetothermal-induced CRISPR-Cas9 gene editing system for the targeted knockout of HSP70 and BCL2 genes, thereby enhancing tumor cell apoptosis. The magnetothermal nanoparticulate platform is composed of superparamagnetic ZnCoFe2O4@ZnMnFe2O4 nanoparticles and the modified polyethyleneimine (PEI) and hyaluronic acid (HA) on the surface, on which plasmid DNA can be effectively loaded. Under the induction of a controllable alternating magnetic field, the mild magnetothermal effect (42℃) not only triggers dual-genome editing to disrupt the apoptosis resistance mechanism of tumor cells but also sensitizes tumor cells to apoptosis through the heat effect itself, achieving a synergistic therapeutic effect. This strategy can precisely regulate the activation of the CRISPR-Cas9 system for tumor cell apoptosis without inducing significant damage to healthy tissues, thus providing a new avenue for cancer treatment. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: The first total synthesis of talaroconvolutin A (1.1 g obtained) and talarofuranone has been achieved using accessible materials (12 steps, 7.5% and 8.2% yields, respectively). Convergent routes involved intramolecular Diels−Alder reactions in two approaches for creating the decalin moiety. Additionally, an unprecedented DMP‐mediated domino reaction resulted in the deoxy‐tetramic acid system. These syntheses not only establish the absolute configuration of talaroconvolutin A but also enable further collaborative studies of this type of ferroptosis inducers. [ABSTRACT FROM AUTHOR]

Cyclic peptides are an important class of bioactive molecules used as drugs as well as biomolecular probes. Peptide cyclization under the physiological environment, without added chemicals or reagents, would be a highly useful technique for in situ applications. A simple, highly efficient, and green procedure for side-chain to side-chain in situ peptide cyclization is established here at the physiological condition. The methodology further allows the release of small biologically active molecules through peptide self-cyclization. Bioactive molecules, as well as other organic leaving groups (having primary or secondary alcohol as a functional group), were conjugated to a short peptide RXE sequence (X = Pro/Ala/Gly). The peptides were designed to undergo cyclization under physiological conditions and release the covalently attached chemotherapeutic drug and nucleobases, in a controlled manner. In vitro studies were performed in detail, with optimized physiological parameters, to understand the kinetics as well as the mechanism of self-cyclization. The mechanism of action was investigated by HPLC and ESI-Mass spectrometry. The conformational change, due to cyclization of the peptides, was monitored by CD spectroscopy. The present concept of peptide self-cyclization leading to a bond cleavage could be a potential method of delivery of small, bioactive molecules such as chemotherapeutic drugs.

Objective: Elsholtzia, as a folk medicine, has been widely used in Miao, Yi, and Lahu nationalities and Tibetan and Chinese medicines in China. We aimed to elucidate the possible mechanisms of action of flavonoids of Elsholtzia densa Benth. (FIE) on apoptosis in HeLa human cervical cancer cells in vitro. Methods: Gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS) were used to detect the chemical constituents responsible for the effects of FIE. Network pharmacology was employed to predict the active constituents and their targets to explore the mechanism of action of FIE in treating cervical cancer. Cell cycle and apoptosis were detected by flow cytometry. The intracellular reactive oxygen species (ROS) level and the mitochondrial membrane potential were detected in HeLa cells treated with FIE. RT-PCR assays quantified the expression of apoptosis-related genes. Results and Discusssion: A total of 36 and 109 components were identified by GC-MS and LC-MS, respectively. Six active components, including 5-hydroxy-6,7-dimethoxyflavone, baicalein, cirsimaritin, epicatechin, luteolin, and 5,7-dihydroxy-6-methoxy2-phenylchromen-4-onem, were predicted by network pharmacology. The active components may affect the proliferation and apoptosis of HeLa cells through various cancer pathways, such as NF-kB and PI3K-Akt signaling pathways. FIE significantly inhibited colony formation in HeLa cells. We observed an increase in the total population of apoptotic cells and ROS content in HeLa cells. Further, the mitochondrial membrane potential of HeLa cells was significantly decreased. In HeLa cells, the expression levels of apoptosis-related genes, such as cytochrome C, caspase-3, caspase-9, and bax, were increased, while that of bcl-2 was decreased. Moreover, the ultrastructure of the cells exhibited apoptotic characteristics. Numerous vacuoles and the autophagic structure of the damaged mitochondrial organelles were observed in the cytoplasm of HeLa cells. Conclusions: Flavonoids of Elsholtzia densa Benth. showed clear inhibitory activity in HeLa cells and induced HeLa cell apoptosis through the mitochondrial endogenous apoptotic pathway. [ABSTRACT FROM AUTHOR]

In previous works, we demonstrated that tertiary 3‐chloropiperidines are potent chemotherapeutics, alkylating the DNA through the formation of bicyclic aziridinium ions. Herein, we report the synthesis of novel secondary 3‐chloropiperidine analogues. The synthesis incorporates a new procedure to monochlorinate unsaturated primary amines utilizing N‐chlorosuccinimide, while carefully monitoring the temperature to prevent dichlorination. Furthermore, we successfully isolated highly strained bicyclic aziridines by treating the secondary 3‐chloropiperidines with a sufficient amount of base. We conclude this work with a DNA cleavage assay as a proof of principle, comparing our previously known substrates to the novel compounds. In this, the secondary 3‐chloropiperidine as well as the isolated bicyclic aziridine, proved to be more effective than their tertiary counterpart. [ABSTRACT FROM AUTHOR]

New phenylacetic acid derivatives with potentially valuable biological activities and the ability to act as starting materials for various functionalizations have been prepared by a multi-step synthesis. Starting from 2,6-dibromo-4-methylaniline, the synthetic route involves the construction of the basic aromatic structure (3,4,5-triphenyltoluene) (two steps), followed by its conversion into 2-[(3,4,5-triphenyl)phenyl]acetic acid and derivatives (up to five steps). Based on this multi-step synthesis, five compounds not previously reported in the literature were synthesized; the literature-known 3,4,5-triphenyltoluene was synthesized for the first time in the manner described. This synthesis is applicable for the preparation of numerous new representatives of this class of compounds. [ABSTRACT FROM AUTHOR]

Hydrolytically stable PdII and PtII complexes supported by acyclic diaminocarbene ligands represent a novel class of structural organometallic anticancer agents exhibiting nanomolar antiproliferative activity in a panel of cancer cell lines (IC50 0.07–0.81 μM) and up to 300‐fold selectivity for cancer cells over normal primary fibroblasts. The lead drug candidate was 300 times more potent than cisplatin in vitro and showed higher efficacy in reducing the growth of aggressive MDA‐MB‐231 xenograft tumors in mice. [ABSTRACT FROM AUTHOR]

Probing biomolecular interactions at cellular interfaces is crucial for understanding and interfering with life processes. Although affinity binders with site specificity for membrane proteins are unparalleled molecular tools, a high demand remains for novel multi‐functional ligands. In this study, a synthetic peptide (APQQ) with tight and specific binding to the untargeted extracellular loop of CD81 evolved from a genetically encoded peptide pool. With tailored affinity, APQQ flexibly accesses, site‐specifically binds, and forms a complex with CD81, enabling in‐situ tracking of the dynamics and activity of this protein in living cells, which has rarely been explored because of the lack of ligands. Furthermore, APQQ triggers the relocalization of CD81 from diffuse to densely clustered at cell junctions and modulates the interplay of membrane proteins at cellular interfaces. Motivated by these, efficient suppression of cancer cell migration, and inhibition of breast cancer metastasis were achieved in vivo. [ABSTRACT FROM AUTHOR]

An efficient synthetic approach based on the chelate methodology and difluoroboron complexes was developed for estrone derivatives containing pyrazolo[1,5-a]pyrimidine substituents at the side chain of ring A. [ABSTRACT FROM AUTHOR]

Real‐time monitoring of hydroxyl radical (⋅OH) generation is crucial for both the efficacy and safety of chemodynamic therapy (CDT). Although ⋅OH probe‐integrated CDT agents can track ⋅OH production by themselves, they often require complicated synthetic procedures and suffer from self‐consumption of ⋅OH. Here, we report the facile fabrication of a self‐monitored chemodynamic agent (denoted as Fc‐CD‐AuNCs) by incorporating ferrocene (Fc) into β‐cyclodextrin (CD)‐functionalized gold nanoclusters (AuNCs) via host–guest molecular recognition. The water‐soluble CD served not only as a capping agent to protect AuNCs but also as a macrocyclic host to encapsulate and solubilize hydrophobic Fc guest with high Fenton reactivity for in vivo CDT applications. Importantly, the encapsulated Fc inside CD possessed strong electron‐donating ability to effectively quench the second near‐infrared (NIR‐II) fluorescence of AuNCs through photoinduced electron transfer. After internalization of Fc‐CD‐AuNCs by cancer cells, Fenton reaction between redox‐active Fc quencher and endogenous hydrogen peroxide (H2O2) caused Fc oxidation and subsequent NIR‐II fluorescence recovery, which was accompanied by the formation of cytotoxic ⋅OH and therefore allowed Fc‐CD‐AuNCs to in situ self‐report ⋅OH generation without undesired ⋅OH consumption. Such a NIR‐II fluorescence‐monitored CDT enabled the use of renal‐clearable Fc‐CD‐AuNCs for efficient tumor growth inhibition with minimal side effects in vivo. [ABSTRACT FROM AUTHOR]

Antibody drug conjugates (ADCs) with twelve FDA approved drugs, known as a novel category of anti-neoplastic treatment created to merge the monoclonal antibody specificity with cytotoxicity effect of chemotherapy. However, despite many undeniable advantages, ADCs face certain problems, including insufficient internalization after binding, complex structures and large size of full antibodies especially in targeting of solid tumors. Camelid single domain antibody fragments (Nanobody®) offer solutions to this challenge by providing nanoscale size, high solubility and excellent stability, recombinant expression in bacteria, in vivo enhanced tissue penetration, and conjugation advantages. Here, an anti-human CD22 Nanobody was expressed in E.coli cells and conjugated to Mertansine (DM1) as a cytotoxic payload. The anti-CD22 Nanobody was expressed and purified by Ni–NTA resin. DM1 conjugated anti-CD22 Nanobody was generated by conjugation of SMCC-DM1 to Nanobody lysine groups. The conjugates were characterized using SDS-PAGE and Capillary electrophoresis (CE-SDS), RP-HPLC, and MALDI-TOF mass spectrometry. Additionally, flow cytometry analysis and a competition ELISA were carried out for binding evaluation. Finally, cytotoxicity of conjugates on Raji and Jurkat cell lines was assessed. The drug-to-antibody ratio (DAR) of conjugates was calculated 2.04 using UV spectrometry. SDS-PAGE, CE-SDS, HPLC, and mass spectrometry confirmed conjugation of DM1 to the Nanobody. The obtained results showed the anti-CD22 Nanobody cytotoxicity was enhanced almost 80% by conjugation with DM1. The binding of conjugates was similar to the non-conjugated anti-CD22 Nanobody in flow cytometry experiments. Concludingly, this study successfully suggest that the DM1 conjugated anti-CD22 Nanobody can be used as a novel tumor specific drug delivery system. [ABSTRACT FROM AUTHOR]

The single‐functionality of traditional chemodynamic therapy (CDT) reagents usually limits the therapeutic efficacy of cancer treatment. Synergistic nanocomposites that involve cascade reaction provide a promising strategy to achieve satisfactory anticancer effects. Herein, a cuprous‐based nanocomposite (CCS@GOx@HA) is fabricated, which owns the tumor targeting ability and can undergo tumor microenvironment responsive cascade reaction to enhance the tumor therapeutic efficiency significantly. Surface modification of nanocomposite with hyaluronic acid enables the targeted delivery of the nanocomposite to cancer cells. Acid‐triggered decomposition of nanocomposite in cancer cell results in the release of Cu+, Se2− and GOx. The Cu+ improves the Fenton‐like reaction with endogenous H2O2 to generate highly toxic • OH for CDT. While GOx can not only catalyze the in situ generation of endogenous H2O2, but also accelerate the consumption of intratumoral glucose to reduce nutrient supply in tumor site. In addition, Se2− further improves the therapeutic effects of CDT by upregulating the reactive oxygen species (ROS) in tumor cells. Meanwhile, the surface modification endows the nanocomposite the good water dispersibility and biocompatibility. Moreover, in vitro and in vivo experiments demonstrate satisfactory anti‐cancer therapeutic performance by the synergistic cascade function of CCS@GOx@HA than CDT alone. [ABSTRACT FROM AUTHOR]

Aliphatic amines containing N-heterocyclic fragments reacted with dialkyl [3,5-di-tert-butyl-4-oxo-2,5-cyclohexadienylidene)methyl] phosphonates to form 1,6-nucleophilic addition products. This approach was used to obtain α-aminophosphonates containing sterically hindered phenol and N-heterocyclic fragments in high yields. All the compounds were evaluated for their in vitro cytotoxicity with various cancer cell lines by MTT assay method. In the course of biological studies, it was found that the obtained compounds possess cytotoxic activity against some tumor cells. [ABSTRACT FROM AUTHOR]

Cholangiocarcinoma (CCA) is a difficult-to-treat cancer, with limited therapeutic options and surgery being the only curative treatment. Standard chemotherapy involves gemcitabine-based therapies combined with cisplatin, oxaliplatin, capecitabine, or 5-FU with a dismal prognosis for most patients. Receptor tyrosine kinases (RTKs) are aberrantly expressed in CCAs encompassing potential therapeutic opportunity. Hence, 112 RTK inhibitors were screened in KKU-M213 cells, and ceritinib, an approved targeted therapy for ALK-fusion gene driven cancers, was the most potent candidate. Ceritinib's cytotoxicity in CCA was assessed using MTT and clonogenic assays, along with immunofluorescence, western blot, and qRT-PCR techniques to analyze gene expression and signaling changes. Furthermore, the drug interaction relationship between ceritinib and cisplatin was determined using a ZIP synergy score. Additionally, spheroid and xenograft models were employed to investigate the efficacy of ceritinib in vivo. Our study revealed that ceritinib effectively killed CCA cells at clinically relevant plasma concentrations, irrespective of ALK expression or mutation status. Ceritinib modulated multiple signaling pathways leading to the inhibition of the PI3K/Akt/mTOR pathway and activated both apoptosis and autophagy. Additionally, ceritinib and cisplatin synergistically reduced CCA cell viability. Our data show ceritinib as an effective treatment of CCA, which could be potentially explored in the other cancer types without ALK mutations. [ABSTRACT FROM AUTHOR]

Simple Summary: This work describes the synthesis and characterization of four small-molecule derivatives based on the 1,10-phenanthroline heterocyclic system as potential telomeric quadruplex DNA ligands with antitumor properties. DNA-ligand interaction studies were carried out to determine thermal stabilization, structural effects and binding affinity towards the human telomeric DNA sequence Tel22. Cytotoxicity in tumor and normal cells was preliminarily tested, along with alterations in cell cycle and the ability to induce apoptosis. Three of the studied compounds can bind and stabilize the telomeric quadruplex sequence and exhibit moderate cytotoxicity in tumor cells. In addition, they were shown to induce apoptosis in HeLa cells, which highlights their potential applications as chemical tools for the development of novel antitumor agents. Four 1,10-phenanthroline derivatives (1–4) were synthesized as potential telomeric DNA binders, three substituted in their chains with thiosemicarbazones (TSCs) and one 4-phenylthiazole derivative. The compounds were characterized using NMR, HRMS, FTIR-spectroscopy and combustion elemental analysis. Quadruplex and dsDNA interactions were preliminarily studied, especially for neutral derivative 1, using FRET-based DNA melting assays, equilibrium dialysis (both competitive and non-competitive), circular dichroism and viscosity titrations. The TSC derivatives bind and stabilize the telomeric Tel22 quadruplex more efficiently than dsDNA, with an estimated 24-fold selectivity determined through equilibrium dialysis for compound 1. In addition, cytotoxic activity against various tumor cells (PC-3, DU145, HeLa, MCF-7 and HT29) and two normal cell lines (HFF-1 and RWPE-1) was evaluated. Except for the 4-phenylthiazole derivative, which was inactive, the compounds showed moderate cytotoxic properties, with the salts displaying lower IC50 values (30–80 μM), compared to the neutral TSC, except in PC-3 cells (IC50 (1) = 18 μM). However, the neutral derivative was the only compound that exhibited a modest selectivity in the case of prostate cells (tumor PC-3 versus healthy RWPE-1). Cell cycle analysis and Annexin V/PI assays revealed that the compounds can produce cell death by apoptosis, an effect that has proven to be similar to that demonstrated by other known 1,10-phenanthroline G4 ligands endowed with antitumor properties, such as PhenDC3 and PhenQE8. [ABSTRACT FROM AUTHOR]

Inhibition of angiogenesis is one of the significant contrivance to suppress the developing tumor. Several previous studies have shown that phytochemicals can modify numerous vital processes of tumor promotion. However, there is no literature evidence of investigation on antitumor and antiangiogenic activity of Citrus karna Raf. fruit. It is used as folklore medicine for the treatment of various conditions like diabetic complications, gastro-intestinal disorders and neurological complication by the rural peoples in India. The present study was performed to investigate antitumor and antiangiogenic activity of Citrus Karna Raf. fruit peel. Among the different extracts, the CKME showed strong in vitro cytotoxic activity on Human Lung Cancer Cell line Hop2 and Human Hepatoma Cell line HepG2 in SRB assay. In Chick embryo chorioallantoic membrane (CAM) assay, angiogenesis processes is strongly inhibited by CKME and chrysin at 100 μg/disc. The formation of blood vessels is essential for fulfilling tumor growth requirements and transport of metastatically competent tumor cells that was reduced by CKME and chrysin. In silico PASS prediction showed that of Citrus Karna Raf. contains several phytochemicals that exhibit anticancer active by different mechanisms like inhibition of TNF expression and stimulation of apoptosis. In conclusion, the components of CKME are promising candidates for cancer treatment and further experimental investigations are needed in order to confirm their mechanism of action. [ABSTRACT FROM AUTHOR]

New phenylacetic acid derivatives with potentially valuable biological activities and the ability to act as starting materials for various functionalizations have been prepared by a multi-step synthesis. Starting from 2,6-dibromo-4-methylaniline, the synthetic route involves the construction of the basic aromatic structure (3,4,5-triphenyltoluene) (two steps), followed by its conversion into 2-[(3,4,5-triphenyl)phenyl]acetic acid and derivatives (up to five steps). Based on this multi-step synthesis, five compounds not previously reported in the literature were synthesized; the literature-known 3,4,5-triphenyltoluene was synthesized for the first time in the manner described. This synthesis is applicable for the preparation of numerous new representatives of this class of compounds.

Abstract In previous works, we demonstrated that tertiary 3‐chloropiperidines are potent chemotherapeutics, alkylating the DNA through the formation of bicyclic aziridinium ions. Herein, we report the synthesis of novel secondary 3‐chloropiperidine analogues. The synthesis incorporates a new procedure to monochlorinate unsaturated primary amines utilizing N‐chlorosuccinimide, while carefully monitoring the temperature to prevent dichlorination. Furthermore, we successfully isolated highly strained bicyclic aziridines by treating the secondary 3‐chloropiperidines with a sufficient amount of base. We conclude this work with a DNA cleavage assay as a proof of principle, comparing our previously known substrates to the novel compounds. In this, the secondary 3‐chloropiperidine as well as the isolated bicyclic aziridine, proved to be more effective than their tertiary counterpart.

Bacterial extracellular vesicles (BEVs), bacteria-derived extracellular vesicles, are key intermediates of bacteria-bacteria and bacteria-host interactions. They are a 'double-edged sword'. On one hand, they play a negative role in the onset and progression of various diseases, including intestinal inflammatory disease, neurological disease, liver disease, metabolic disease, autoimmune disease and cancer. On the other hand, they play a positive role as potential biomarkers, vaccines, antitumor agents. The application of BEVs may provide novel strategies for the diagnosis and treatment of diseases. However, research on BEVs is still in its infancy, and challenges remain in vesicle isolation techniques, disease diagnostic specificity, optimization of vesicle storage and transport. Thus rigorously designed clinical studies are required to verify their diagnostic and therapeutic value.

Background: Actinomycetes particularly the Streptomyces sp. derived from marine and coastal habitats are regarded as the main source of antibiotics. In the current study, to isolate the antibiotic-producing actinomycetes sediment samples were collected from Manakudy estuary, Kanyakumari District, Tamil Nadu. Results: The isolates were selected based on the antagonistic activity; the highly active isolate was identified as Streptomyces sp. CMSTAAHL-3. The culture media for the antibiotic production was optimized by one variable at a time and confirmed by the zone of inhibition against tested pathogens such as Staphylococcus aureus, Enterococcus faecalis, Klebsiella pneumoniae, Escherichia coli, and Pseudomonas aeruginosa. Then by altering the four factors starch, urea, MgSO4 and NaCl at five levels, statistical optimization of the media components was explored using Response Surface Methodology-Central Composite Design and found that the predicted antibiotic response was closely correlated with the experimentally one and was confirmed by the zone of inhibition. Conclusions: The Streptomyces sp. CMSTAAHL-3 and its antibiotics may be of great use in the treatment of a variety of pathogens, and the ideal culture medium discovered in this experiment will be helpful for further research involving large-scale fermentation for the effective production of antibiotics.How to cite: Selvaraj JN, Ganapathi U, Vincent SGP, et al. Statistical optimization of media components for antibiotic production in Streptomyces sp. CMSTAAHAL-3. Electron J Biotechnol 2023;64. https://doi.org/10.1016/j.ejbt.2023.03.005.

The total synthesis of the proposed structure of anti‐glioblastoma natural product neaumycin B was achieved in 22 steps (longest linear sequence). The synthesis features HCl‐mediated [6,6]‐spiroketalization, a combination of Krische iridium‐catalyzed crotylation, Marshall palladium‐catalyzed propargylation, Fürstner nickel‐catalyzed regio‐ and enantioselective vicinal monoprotected diol formation, Brown crotylation and asymmetric halide‐aldehyde cycloaddition, so as to establish the challenging contiguous stereocenters. [ABSTRACT FROM AUTHOR]

Simple Summary: Soft tissue sarcomas represent a large heterogeneous group of malignant neoplasms that are characterized by a poor disease outcome and being poorly studied. Recently, more and more studies have been directed to the role of tumor microenvironment components in establishing the aggressive potential of the tumor. Many antitumor drugs, in addition to their direct effect on tumor cells, modify the tumor microenvironment; in particular, they act on the immune component, which may be the reason for their effectiveness in soft tissue sarcoma. Immune cells themselves are now considered as promising antitumor strategies for the treatment of soft tissue sarcomas. Understanding the mechanisms of interaction between tumor cells and immune cells in different types of soft tissue sarcomas will allow us to divide patients into those for whom immunotherapy will be highly effective and those for whom this type of treatment will be ineffective. Soft tissue sarcomas (STSs) are a rare heterogeneous group of malignant neoplasms characterized by their aggressive course and poor response to treatment. This determines the relevance of research aimed at studying the pathogenesis of STSs. By now, it is known that STSs is characterized by complex relationships between the tumor cells and immune cells of the microenvironment. Dynamic interactions between tumor cells and components of the microenvironment enhance adaptation to changing environmental conditions, which provides the high aggressive potential of STSs and resistance to antitumor therapy. Today, active research is being conducted to find effective antitumor drugs and to evaluate the possibility of using therapy with immune cells of STS. The difficulty in assessing the efficacy of new antitumor options is primarily due to the high heterogeneity of this group of malignant neoplasms. Studying the role of immune cells in the microenvironment in the progression STSs and resistance to antitumor therapies will provide the discovery of new biomarkers of the disease and the prediction of response to immunotherapy. In addition, it will help to initially divide patients into subgroups of good and poor response to immunotherapy, thus avoiding wasting precious time in selecting the appropriate antitumor agent. [ABSTRACT FROM AUTHOR]

In this work, new isatin-based sulphonamides (6a-i, 11a-c, 12a-c) were designed and synthesised as potential dual VEGFR-2 and carbonic anhydrase inhibitors with anticancer activities. Firstly, all target isatins were examined for in vitro antitumor action on NCI-USA panel (58 tumour cell lines). Then, the most potent derivatives were examined for the potential CA inhibitory action towards the physiologically relevant hCA isoforms I, II, and tumour-linked hCA IX isoform, in addition, the VEGFR-2 inhibitory activity was evaluated. The target sulphonamides failed to inhibit the CA isoforms that could be attributable to the steric effect of the neighbouring methoxy group, whereas they displayed potent VEGFR-2 inhibitory effect. Following that, isatins 11b and 12b were tested for their influence on the cell cycle disturbance, and towards the apoptotic potential. Finally, detailed molecular modelling analyses, including docking and molecular dynamics, were carried out to assess the binding mode and stability of target isatins. [ABSTRACT FROM AUTHOR]

Twenty-five azole compounds (P1–P25) were synthesised using regioselective base-metal catalysed and microwave-assisted approaches, fully characterised by high-resolution mass spectrometry (HRMS), nuclear magnetic resonance (NMR), and infrared spectra (IR) analyses, and evaluated for anticancer, anti-tyrosinase, and anti-oxidant activities in silico and in vitro. P25 exhibited potent anticancer activity against cells of four skin cancer (SC) lines, with selectivity for melanoma (A375, SK-Mel-28) or non-melanoma (A431, SCC-12) SC cells over non-cancerous HaCaT-keratinocytes. Clonogenic, scratch-wound, and immunoblotting assay data were consistent with anti-proliferative results, expression profiling therewith implicating intrinsic and extrinsic apoptosis activation. In a mushroom tyrosinase inhibition assay, P14 was most potent among the compounds (half-maximal inhibitory concentration where 50% of cells are dead, IC50 15.9 μM), with activity greater than arbutin and kojic acid. Also, P6 exhibited noteworthy free radical-scavenging activity. Furthermore, in silico docking and absorption, distribution, metabolism, excretion, and toxicity (ADMET) simulations predicted prominent-phenotypic actives to engage diverse cancer/hyperpigmentation-related targets with relatively high affinities. Altogether, promising early-stage hits were identified – some with multiple activities – warranting further hit-to-lead optimisation chemistry with further biological evaluations, towards identifying new skin-cancer and skin-pigmentation renormalising agents. [ABSTRACT FROM AUTHOR]

A series of eight new phosphonamidates containing sterically hindered phenolic and N-heterocyclic fragments was obtained and characterized. The synthesis is based on the reaction of O-alkyl-3,5-di-tert-butyl-4-hydroxybenzylchlorophosphonates with aliphatic amines. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: Based on characteristics of the tumor microenvironment (TME), including acidity, hypoxia, inflammation and hydrogen peroxide overload, combined with emerging nanotechnologies, designing nanoplatforms with TME specificity/responsiveness for tumor treatment is a promising nanotherapeutic strategy. In this work, a multifunctional gold‐palladium bimetallic cascade nanozyme was constructed for effective photothermal‐enhanced cascade catalyzed synergistic therapy of tumors. The dumbbell‐like Au‐Pd bimetallic nanomaterial (Au NRs‐Pd@HA) was obtained by reducing palladium on gold nanorods with ascorbic acid (AA) and further modified with hyaluronic acid (HA). The introduction of HA brings biocompatibility and targeting properties. The zebrafish embryos model showed that Au NRs‐Pd@HA had good biocompatibility and low biotoxicity. Au NRs‐Pd@HA can induce catalytic conversion of glucose to generate H2O2 efficiently, and subsequently undergo cascade reaction to produce abundant ·OH radicals, exhibiting peroxidase‐like (POD‐like) and glucose oxidase‐like (GOD‐like) capabilities. The generated ·OH was a key factor for tumor ablation. Meanwhile, Au NRs‐Pd@HA exhibits good photothermal performance under 808 nm irradiation, in favor of photothermal therapy (PTT). Especially, the POD‐like and GOD‐like activities were significantly enhanced due to the photothermal effect. The synergistic PTT and photothermal‐enhanced nanozymes with cascade catalytic effect enabled efficient and safe cancer therapy. [ABSTRACT FROM AUTHOR]

This work describes the synthesis of four gold(I) [AuClL] compounds containing chloro and biologically active protonated thiosemicarbazones based on 5‐nitrofuryl (L=HSTC). The stability of the compounds in dichloromethane, DMSO, and DMSO/culture media solutions was investigated by spectroscopy, cyclic voltammetry, and conductimetry, indicating the formation overtime of cationic monometallic [Au(HTSC)(DMSO)]± or [Au(HTSC)2]±, and/or dimeric species. Neutral [{Au(TSC)}2] species were obtained from one of the compounds in dichlomethane/n‐hexane solution and characterized by X‐ray crystallography revealing a Au−Au bond, and deprotonated thiosemicarbazone (TSC). The cytotoxicity of the gold compounds and thiosemicarbazone ligands was evaluated against selected cancer cell lines and compared to that of Auranofin. Studies of the most stable, cytotoxic, and selective compound on a renal cancer cell line (Caki‐1) demonstrated its relevant antimigratory and anti‐angiogenic properties, and preferential accumulation in the cell nuclei. Its mode of action seems to involve interaction with DNA, and subsequent cell death via apoptosis. [ABSTRACT FROM AUTHOR]

Platinum(IV) prodrugs are highly interesting alternatives to platinum(II) anticancer therapeutics due to their increased tumor selectivity and reduced side effects. In contrast to the established theory, we recently observed that the equatorial ligand(s) of e.g. oxaliplatin(IV) complexes can be hydrolyzed with formation of [(DACH)Pt(OHeq)2(OAcax)2]. In the work presented here, we investigated the reactivity and synthetic usability of this complex to be exploited as a precursor for the development of novel platinum(IV) complexes, not able to be synthesized by conventional protocols. Indeed, we could substitute the equatorial hydroxido ligand(s) e.g. by one or two monodentate biotin ligands (which would be oxidized under standard methods). The formed complexes turned out to be very stable with slow ligand release after reduction, ideal for long‐circulating tumor‐targeting strategies. Therefore, two platinum(IV) complexes with equatorial maleimides, capable of exploiting serum albumin as a natural nanocarrier, were synthesized as well. The complexes showed massively prolonged plasma half‐life and distinctly improved anticancer activity in vivo compared to oxaliplatin. Taken together, the newly developed synthetic platform allows the simple and specific insertion of equatorial ligands into platinum(IV) complexes. This will enable the attachment of three different (bioactive) moieties generating targeted triple‐action platinum(IV) prodrugs within one single platinum complex. [ABSTRACT FROM AUTHOR]

A series of four binuclear complexes of general formula [(C^C)Au(Cl)(L^L)(Cl)Au(C^C)], where C^C is 4,4'‐diterbutylbiphenyl and L^L is either a bridging diphosphine or 4,4'‐bipyridine, are synthetized with 52 to 72 % yield and structurally characterized by X‐ray diffraction. The use of the chelating 1,2‐diphenylphosphinoethane ligand in a 1 : 2 (P^P):Au stoichiometry leads to the near quantitative formation of a gold double‐complex salt of general formula [(C^C)Au(P^P)][(C^C^)AuCl2]. The compounds display long‐lived yellow‐green phosphorescence with λem in the range of 525 to 585 nm in the solid state with photoluminescence quantum yields (PLQY) up to 10 %. These AuIII complexes are tested for their antiproliferative activity against lung adenocarcinoma cells A549 and results show that compounds 2 and 5 are the most promising candidates. The digold salt 5 shows anticancer activity between 66 and 200 nM on the tested cancer cell lines, whereas derivative 2 displays concentration values required to reduce by 50 % the cell viability (IC50) between 7 and 11 μM. Reactivity studies of compound 5 reveal that the [(C^C)Au(P^P)]+ cation is stable in the presence of relevant biomolecules including glutathione suggesting a structural mechanism of action. [ABSTRACT FROM AUTHOR]

A library of 24 congeners of the natural product sulfuretin were evaluated against nine panels representing nine cancer diseases. While sulfuretin elicited very weak activities at 10 µM concentration, congener 1t was identified as a potential compound triggering growth inhibition of diverse cell lines. Mechanistic studies in HCT116 colon cancer cells revealed that congener 1t dose-dependently increased levels of cleaved-caspases 8 and 9 and cleaved-PARP, while it concentration-dependently decreased levels of CDK4, CDK6, Cdc25A, and Cyclin D and E resulting in induction of cell cycle arrest and apoptosis in colon cancer HCT116 cells. Mechanistic study also presented MET receptor tyrosine kinase as the molecular target mediating the anticancer activity of compound 1t in HCT116 cells. In silico study predicted folded p-loop conformation as the form of MET receptor tyrosine kinase responsible for binding of compound 1t. Together, the current study presents compound 1t as an interesting anticancer lead for further development. [ABSTRACT FROM AUTHOR]

In our previous study, we described the batch synthesis of CPL304110, an innovative pan-FGFR inhibitor. Herein, we transferred the Claisen condensation reaction, one of the synthesis steps to a continuous flow reactor. A simple solvent switch from ethanol to tetrahydrofuran shortened the original reaction time from 20 h to 10 min. With the use of the design of experiment method and program Statistica®, we optimized reaction parameters and increased the reaction yields from 73 to 84% with greatly shortened reaction times (20 h vs. 2 min), improved productivity (74.4 g h−1), and increased space–time yield (3720 kg h−1 m−3). [ABSTRACT FROM AUTHOR]

Many microRNAs (miRNAs) are characteristically found in cancer cells, making miRNAs promising marker biomolecules for cancer diagnosis and therapeutics. However, it is challenging to use miRNA as a cancer signature because it is difficult to convert the nucleic acid sequence information into molecular functionality. To address this challenge, we realize nucleic acid‐to‐small molecule converters using hairpin DNA circuits. Harnessing a Staudinger reduction as a trigger for the conversion, we constructed hybridization chain reaction (HCR) and catalytic hairpin assembly (CHA) circuits that respond to oncogenic miR‐21. Fluorophore and dye molecules were released in response to miR‐21 through the HCR, providing fluorogenic and chromogenic readouts. Selective cytotoxicity in miR‐21‐abundant cells was realized by the CHA to release the anticancer drug SN‐38. This would be the first example of selective activation of a small‐molecule prodrug triggered by oncogenic miRNA in human living cells. [ABSTRACT FROM AUTHOR]

Poly(ADP‐ribose)polymerase‐1 (PARP‐1) is a promising target for antitumor agents. This study presents the first evidence of hydroxamic acids as efficient PARP inhibitors. Molecular docking and molecular dynamics simulations revealed that N−O substituted phenanthridinones form a complex interplay with PARP‐1. A series of cyclic aryl hydroxamic acids, N‐(benzyloxy)‐ and N‐(hydroxy)phenanthridinones, were prepared through a ligand‐free methodology from N‐(benzyloxy)benzamides using dual C−H/N−H bond activation. Three of the computed hit compounds exhibited significant activity in cell‐based and enzymatic assays, inhibiting PARP‐1 in the low‐nanomolar range. The antiproliferative activity of all prepared compounds and the reference compounds PJ34 and Olaparib was evaluated in cancer cells (HepG2, BxPC3, MDA‐MD‐231, and HeLa) and in noncancer cell lines (NIH 3T3 and HEK 293). An N‐(benzyloxy)‐ and an N‐(hydroxy)phenanthridinone showed the most promising properties as leads for developing therapeutics with a submicromolar activity window. The study highlights the potential utility of this scaffold for PARP inhibitors and the importance of target‐specific design to minimize toxicity and side effects. [ABSTRACT FROM AUTHOR]

Twenty-five azole compounds (P1–P25) were synthesised using regioselective base-metal catalysed and microwave-assisted approaches, fully characterised by high-resolution mass spectrometry (HRMS), nuclear magnetic resonance (NMR), and infrared spectra (IR) analyses, and evaluated for anticancer, anti-tyrosinase, and anti-oxidant activities in silico and in vitro. P25 exhibited potent anticancer activity against cells of four skin cancer (SC) lines, with selectivity for melanoma (A375, SK-Mel-28) or non-melanoma (A431, SCC-12) SC cells over non-cancerous HaCaT-keratinocytes. Clonogenic, scratch-wound, and immunoblotting assay data were consistent with anti-proliferative results, expression profiling therewith implicating intrinsic and extrinsic apoptosis activation. In a mushroom tyrosinase inhibition assay, P14 was most potent among the compounds (half-maximal inhibitory concentration where 50% of cells are dead, IC50 15.9 μM), with activity greater than arbutin and kojic acid. Also, P6 exhibited noteworthy free radical-scavenging activity. Furthermore, in silico docking and absorption, distribution, metabolism, excretion, and toxicity (ADMET) simulations predicted prominent-phenotypic actives to engage diverse cancer/hyperpigmentation-related targets with relatively high affinities. Altogether, promising early-stage hits were identified – some with multiple activities – warranting further hit-to-lead optimisation chemistry with further biological evaluations, towards identifying new skin-cancer and skin-pigmentation renormalising agents.

In this work, new isatin-based sulphonamides (6a-i, 11a-c, 12a-c) were designed and synthesised as potential dual VEGFR-2 and carbonic anhydrase inhibitors with anticancer activities. Firstly, all target isatins were examined for in vitro antitumor action on NCI-USA panel (58 tumour cell lines). Then, the most potent derivatives were examined for the potential CA inhibitory action towards the physiologically relevant hCA isoforms I, II, and tumour-linked hCA IX isoform, in addition, the VEGFR-2 inhibitory activity was evaluated. The target sulphonamides failed to inhibit the CA isoforms that could be attributable to the steric effect of the neighbouring methoxy group, whereas they displayed potent VEGFR-2 inhibitory effect. Following that, isatins 11b and 12b were tested for their influence on the cell cycle disturbance, and towards the apoptotic potential. Finally, detailed molecular modelling analyses, including docking and molecular dynamics, were carried out to assess the binding mode and stability of target isatins.

NAD(P)H:quinone acceptor oxidoreductase 1 (NQO1), a detoxifying enzyme overexpressed in tumors, plays a key role in protecting cancer cells against oxidative stress and thus has been considered an attractive candidate for activating prodrug(s). Herein, we report the first use of NQO1 for the selective activation of 'protransporter' systems in cancer cells leading to the induction of apoptosis. Salicylamides, easily synthesizable small molecules, have been effectively used for efficient H+/Cl− symport across lipid membranes. The ion transport activity of salicylamides was efficiently abated by caging the OH group with NQO1 activatable quinones via either ether or ester linkage. The release of active transporters, following the reduction of quinone caged 'protransporters' by NQO1, was verified. Both the transporters and protransporters exhibited significant toxicity towards the MCF‐7 breast cancer line, mediated via the induction of oxidative stress, mitochondrial membrane depolarization, and lysosomal deacidification. Induction of cell death via intrinsic apoptotic pathway was verified by monitoring PARP1 cleavage. [ABSTRACT FROM AUTHOR]

Background: Actinomycetes particularly the Streptomyces sp. derived from marine and coastal habitats are regarded as the main source of antibiotics. In the current study, to isolate the antibiotic-producing actinomycetes sediment samples were collected from Manakudy estuary, Kanyakumari District, Tamil Nadu. Results: The isolates were selected based on the antagonistic activity; the highly active isolate was identified as Streptomyces sp. CMSTAAHL-3. The culture media for the antibiotic production was optimized by one variable at a time and confirmed by the zone of inhibition against tested pathogens such as Staphylococcus aureus, Enterococcus faecalis, Klebsiella pneumoniae, Escherichia coli, and Pseudomonas aeruginosa. Then by altering the four factors starch, urea, MgSO4 and NaCl at five levels, statistical optimization of the media components was explored using Response Surface Methodology-Central Composite Design and found that the predicted antibiotic response was closely correlated with the experimentally one and was confirmed by the zone of inhibition. Conclusions: The Streptomyces sp. CMSTAAHL-3 and its antibiotics may be of great use in the treatment of a variety of pathogens, and the ideal culture medium discovered in this experiment will be helpful for further research involving large-scale fermentation for the effective production of antibiotics. [ABSTRACT FROM AUTHOR]

Tetrakis(4‐aminophenyl)porphyrin (1) and tetrakis(4‐acetamidophenyl)porphyrin (2) were dissolved in water with the incorporation of a polysaccharide (λ‐carrageenan (CGN)) as a water‐solubilizing agent. Although the photodynamic activity of the CGN‐2 complex was considerably lower than that of the CGN‐1 complex, the selectivity index (SI; IC50 in a normal cell/IC50 in a cancer cell) of the CGN‐2 complex was considerably higher than that of the CGN‐1 complex. This is because the photodynamic activity of the CGN‐2 complex was significantly affected by the intracellular uptakes by the normal and cancer cells. During in vivo experiments, the CGN‐2 complex inhibited tumor growth under light irradiation with high blood retention compared with the CGN‐1 complex and Photofrin, which exhibited lower blood retention. This study showed that the photodynamic activity and SI are influenced by substituent groups of arene in the meso‐positions of porphyrin analogs. [ABSTRACT FROM AUTHOR]

An expanding body of evidence suggests that specifically targeting hydrogen sulfide (H2S) might potentially benefit both tumor diagnosis and treatment, but there is still a lack of cancer‐targeted molecular tools for in vivo applications. Here, we report the first ligand‐directed H2S‐specific near‐infrared fluorescent sensor PSMA‐Cy7‐NBD and scavenger PSMA‐Py‐NBD that target the prostate‐specific membrane antigen (PSMA). PSMA‐Cy7‐NBD displays a 53‐fold off–on fluorescence response to H2S at 803 nm with high specificity. PSMA‐Py‐NBD can scavenge H2S fast (k2=30.8 M−1 s−1 at 25 °C) without interference from biothiols. Both tools are highly water‐soluble and can be transported selectively into PSMA‐expressing prostate cancer cells. Endogenous H2S levels in murine 22Rv1 tumor models can be imaged and downregulated by intravenous injection of PSMA‐Cy7‐NBD and PSMA‐Py‐NBD, respectively. These tools could potentially help to investigate H2S cancer biology and with related therapies. [ABSTRACT FROM AUTHOR]

Introduction: Heterocyclic compounds have diverse biological activities and potential in drug development. This study aims to synthesize novel compounds with two 1,2,4-triazole cores and evaluate their biological properties, particularly their inhibitory activity against thymidine phosphorylase (TP), an enzyme involved in various physiological processes.Methods: The compounds were synthesized by reacting 5,5'-butane-bis-1,2,4-triazole derivatives with prenyl bromide. Characterization involved various techniques, including spectroscopy and elemental analysis. Antimicrobial potential was evaluated against bacteria and fungi, with comparative antibiotics as references. Inhibitory activity against TP was assessed, and molecular docking studies were conducted.Results: Six compounds were successfully synthesized and their structures confirmed. The synthesized triazole derivatives exhibited high biological activity, with compounds 2 and 6 showing the most promising TP inhibition. Molecular docking studies revealed interactions between compound 2 and TP, involving nine amino acids.Discussion: The synthesis of novel compounds with two 1,2,4-triazole cores contributes significantly to bis-triazole research. These compounds have potential as anti-tumor agents due to their inhibitory activity against TP, a crucial enzyme in tumor growth and metastasis. Comparative evaluation against antibiotics highlights their potency. Docking results provide insights into their interactions with TP, supporting their potential as potent TP inhibitors. Further research should focus on evaluating their efficacy in biological models, understanding their mechanisms of action, and optimizing their activities.Conclusion: The synthesized compounds with two 1,2,4-triazole cores exhibit significant biological activity, including strong TP inhibition and broad-spectrum antimicrobial effects. These findings emphasize their potential as anti-tumor agents and the need for further exploration and optimization. Future research should focus on evaluating their efficacy in biological models, understanding their mechanisms of action, and developing more potent bis-triazole derivatives for drug discovery efforts. The combined results from assays and docking studies support the therapeutic potential of these compounds as anti-tumor agents. [ABSTRACT FROM AUTHOR]