Search

Aminopyrazoles represent interesting structures in medicinal chemistry, and several derivatives showed biological activity in different therapeutic areas. Previously reported 5-aminopyrazolyl acylhydrazones and amides showed relevant antioxidant and anti-inflammatory activities. To further extend the structure–activity relationships in this class of derivatives, a novel series of pyrazolyl acylhydrazones and amides was designed and prepared through a divergent approach. The novel compounds shared the phenylamino pyrazole nucleus that was differently decorated at positions 1, 3, and 4. The antiproliferative, antiaggregating, and antioxidant properties of the obtained derivatives 10–22 were evaluated in in vitro assays. Derivative 11a showed relevant antitumor properties against selected tumor cell lines (namely, HeLa, MCF7, SKOV3, and SKMEL28) with micromolar IC50 values. In the platelet assay, selected pyrazoles showed higher antioxidant and ROS formation inhibition activity than the reference drugs acetylsalicylic acid and N-acetylcysteine. Furthermore, in vitro radical scavenging screening confirmed the good antioxidant properties of acylhydrazone molecules. Overall, the collected data allowed us to extend the structure–activity relationships of the previously reported compounds and confirmed the pharmaceutical attractiveness of this class of aminopyrazole derivatives. [ABSTRACT FROM AUTHOR]

A library of novel coumarin-based triazolyl glycoconjugates is prepared and screened for in vitro antibacterial activity against Gram-positive (Bacillus megaterium) and Gram-negative bacteria (Escherichia coli) via disc diffusion technique in the current study. The biological assays revealed significant antibacterial potential of new synthetic coumarin triazolyl glycoconjugates, compound 5d being the most active one with zones of inhibition (mm) of 34.33 ± 0.88 (10 μg/mL) and 36.66 ± 0.88 (20 μg/mL) against E. coli and 17.66 ± 1.20 (10 μg/mL) and 20 ± 1.15 (20 μg/mL) against B. megaterium. The activity was found comparable to the reference drugs chloramphenicol [36.33 ± 0.88 (10 μg/mL), 38.66 ± 0.88 (20 μg/mL) against E. coli and 25 ± 0.57 (10 μg/mL), 25.33 ± 0.66 (20 μg/mL) against B. megaterium] and ampicillin [32.33 ± 1.71 (10 μg/mL), 34.66 ± 2.40 (20 μg/mL) against E. coli and 20.33 ± 1.85 (10 μg/mL), 23.66 ± 2.33 (20 μg/mL) against B. megaterium]. The coumarin-based triazole analog 5e also displayed selective but moderate antiproliferative activity (growth inhibition ~ 23%) against leukemia cell lines when screened against 60 cancer cell lines at National Cancer Institute, USA. The study leads to the identification of several novel coumarin based compounds with dual anti-proliferative and antibacterial activity profile. [ABSTRACT FROM AUTHOR]

Two new 4-methylcoumarin derivatives (3a–f and 4a–f) were designed, synthesized, and evaluated for their cytotoxic activity. Different spectroscopic methods and elemental analyses confirmed all the synthesized derivatives' characterization. All the prepared compounds were biologically screened against four cancer cell lines (hepatocellular carcinoma HepG-2, colon cancer cell lines HCT-116, breast cancer cell lines MCF-7, and prostate cancer cell lines PC3). The in vitro antiproliferative activity of the target analogues 4b, 4c, 4f, 3b, and 3d against the MCF-7 cancer cell line was significant, with IC50 values of 3.98, 7.80, 10.94, 17.7, and 24.07 μM, respectively. Furthermore, the potent cytotoxic oxime derivative 4b was evaluated for cell cycle analysis showing a significant substantial disruption in cell cycle profile and cell cycle arrest at the S phase boundary with a time-dependent rise in a pre-G cell population, as well as a 22-fold increase in MCF-7 apoptosis compared to control cells. Accordingly, the Bax/Bcl-2 ratio, a critical ratio in controlling cell sensitivity to apoptosis, increased upon treatment with the oxime analog 4b. A docking investigation was conducted within the BcL-2 binding site to explore and anticipate the binding modes of the synthesized compounds. Thus, synthesizing these novel coumarin/nitric oxide hybrids may aid in developing promising antiproliferative agents. [ABSTRACT FROM AUTHOR]

With the aim to combine more than one biologically‐active component in a single molecule, derivatives of ispinesib and its (S) analogue were prepared that featured ferrocenyl moieties or bulky organic substituents. Inspired by the strong kinesin spindle protein (KSP) inhibitory activity of ispinesib, the compounds were investigated for their antiproliferative activity. Among these compounds, several derivatives demonstrated significantly higher antiproliferative activity than ispinesib with nanomolar IC50 values against cell lines. Further evaluation indicated that the antiproliferative activity is not directly correlated with their KSP inhibitory activity while docking suggested that several of the derivatives may bind in a manner similar to ispinesib. In order to investigate the mode of action further, cell cycle analysis and reactive oxygen species formation were investigated. The improved antiproliferative activity of the most active compounds may be assigned to synergic effects of various factors such as KSP inhibitory activity due to the ispinesib core and ability to generate ROS and induce mitotic arrest. [ABSTRACT FROM AUTHOR]

The introduction of selenium (Se) into organic scaffolds has been demonstrated to be a promising framework in the field of medicinal chemistry. A novel design of nonsteroidal anti-inflammatory drug (NSAID) derivatives based on a bioisosteric replacement via the incorporation of Se as diacyl diselenide is reported. The antioxidant activity was assessed using the DPPH radical scavenging assay. The new Se-NSAID derivatives bearing this unique combination showed antioxidant activity in a time- and dose-dependent manner, and also displayed different antiproliferative profiles in a panel of eight cancer cell lines as determined by the MTT assay. Ibuprofen derivative 5 was not only the most antioxidant agent, but also selectively induced toxicity in all the cancer cell lines tested (IC50 < 10 µM) while sparing nonmalignant cells, and induced apoptosis partially without enhancing the caspase 3/7 activity. Furthermore, NSAID derivative 5 significantly suppressed tumor growth in a subcutaneous colon cancer xenograft mouse model (10 mg/kg, TGI = 72%, and T/C = 38%) without exhibiting any apparent toxicity. To our knowledge, this work constitutes the first report on in vitro and in vivo anticancer activity of an unprecedented Se-NSAID hybrid derivative and its rational use for developing precursors for bioisosteric selenocompounds with appealing therapeutic applications. [ABSTRACT FROM AUTHOR]

Aminopyrazoles represent interesting structures in medicinal chemistry, and several derivatives showed biological activity in different therapeutic areas. Previously reported 5-aminopyrazolyl acylhydrazones and amides showed relevant antioxidant and anti-inflammatory activities. To further extend the structure–activity relationships in this class of derivatives, a novel series of pyrazolyl acylhydrazones and amides was designed and prepared through a divergent approach. The novel compounds shared the phenylamino pyrazole nucleus that was differently decorated at positions 1, 3, and 4. The antiproliferative, antiaggregating, and antioxidant properties of the obtained derivatives 10–22 were evaluated in in vitro assays. Derivative 11a showed relevant antitumor properties against selected tumor cell lines (namely, HeLa, MCF7, SKOV3, and SKMEL28) with micromolar IC50 values. In the platelet assay, selected pyrazoles showed higher antioxidant and ROS formation inhibition activity than the reference drugs acetylsalicylic acid and N-acetylcysteine. Furthermore, in vitro radical scavenging screening confirmed the good antioxidant properties of acylhydrazone molecules. Overall, the collected data allowed us to extend the structure–activity relationships of the previously reported compounds and confirmed the pharmaceutical attractiveness of this class of aminopyrazole derivatives.

A series of novel N-methyl-substituted pyrazole carboxamide (10–17) and dicarboxamide derivatives (18–21) were efficiently obtained by the reaction of pyrazole-3-carboxylic acids (4,5) and pyrazole-3,4-dicarboxylic acid (8) with several aromatic and heteroaromatic sulfonamides. Synthesized sulfonamide derivatives were characterized using 1H NMR, 13C NMR, FT-IR, mass spectroscopy techniques. Antiproliferative activities of synthesized molecules were evaluated against the human cervical cancer cell line (HeLa) using the xCELLigence system (Real-Time Analyzer). According to the antiproliferative activity results, compound 16 showed the highest activity among the synthesized compounds with 64.10%, while starting compound 4 showed the highest at all with 80.82%. The methyl substituted pyrazole carboxylic (4) and carboxamide (16) derivatives with antiproliferative activities with 80.82% and 64.10%, respectively, and compound 13 with moderate activity (61.26%) against the human cervical cancer cell line could be a potential lead compounds for developing novel anticancer agents. [ABSTRACT FROM AUTHOR]

Small, strained ring molecules of phenylcyclopropane carboxamide have rigid, defined conformations and unique electronic properties. For these reasons many groups, seek to use these subunits to form biologically active compounds. Herein we report a generally applicable approach for preparing a small cyclopropane ring containing 1-phenylcyclopropane carboxamide derivatives to a wide range of the different aromatic compounds by α-alkylation of 2-phenyl acetonitrile derivatives with 1, 2-dibromo ethane in good yields followed by the conversion of cyano group to acid group by the reaction with concentrated hydrochloric acid. This obtained acid derivative undergoes acid amine coupling with various Methyl 2-(aminophenoxy)acetate to form 1-Phenylcyclopropane Carboxamide. These compounds possess distinct effective inhibition on the proliferation of U937, pro-monocytic, human myeloid leukaemia cell line while these compounds did not show cytotoxic activity on these cells. The structure-activity relationships of these compounds are discussed.

We have carried out the design, synthesis, and evaluation of a small library of 2-aminobenzoxazole-appended coumarins as novel inhibitors of tumour-related CAs IX and XII. Substituents on C-3 and/or C-4 positions of the coumarin scaffold, and on the benzoxazole moiety, together with the length of the linker connecting both units were modified to obtain useful structure-activity relationships. CA inhibition studies revealed a good selectivity towards tumour-associated CAs IX and XII (Ki within the mid-nanomolar range in most of the cases) in comparison with CAs I, II, IV, and VII (Ki > 10 µM); CA IX was found to be slightly more sensitive towards structural changes. Docking calculations suggested that the coumarin scaffold might act as a prodrug, binding to the CAs in its hydrolysed form, which is in turn obtained due to the esterase activity of CAs. An increase of the tether length and of the substituents steric hindrance was found to be detrimental to in vitro antiproliferative activities. Incorporation of a chlorine atom on C-3 of the coumarin moiety achieved the strongest antiproliferative agent, with activities within the low micro-molar range for the panel of tumour cell lines tested. [ABSTRACT FROM AUTHOR]

Two biologically active adamantane-linked hydrazine-1-carbothioamide derivatives, namely 2-(adamantane-1-carbonyl)-N-(tert-butyl)hydrazine-1-carbothioamide) 1 and 2-(adamantane-1-carbonyl)-N-cyclohexylhydrazine-1-carbothioamide 2, have been synthesized. X-ray analysis was conducted to study the effect of the t-butyl and cyclohexyl moieties on the intermolecular interactions and conformation of the molecules in the solid state. X-ray analysis reveals that compound 1 exhibits folded conformation, whereas compound 2 adopts extended conformation. The Hirshfeld surface analysis indicates that the contributions of the major intercontacts involved in the stabilization of the crystal structures do not change much as a result of the t-butyl and cyclohexyl moieties. However, the presence and absence of these contacts is revealed by the 2D-fingerprint plots. The CLP–Pixel method was used to identify the energetically significant molecular dimers. These dimers are stabilized by different types of intermolecular interactions such as N–H···S, N–H···O, C–H···S, C–H···O, H–H bonding and C–H···π interactions. The strength of these interactions was quantified by using the QTAIM approach. The results suggest that N–H···O interaction is found to be stronger among other interactions. The in vitro assay suggests that both compounds 1 and 2 exhibit urease inhibition potential, and these compounds also display moderate antiproliferative activities. Molecular docking analysis shows the key interaction between urease enzyme and title compounds. [ABSTRACT FROM AUTHOR]

The introduction of selenium (Se) into organic scaffolds has been demonstrated to be a promising framework in the field of medicinal chemistry. A novel design of nonsteroidal anti-inflammatory drug (NSAID) derivatives based on a bioisosteric replacement via the incorporation of Se as diacyl diselenide is reported. The antioxidant activity was assessed using the DPPH radical scavenging assay. The new Se-NSAID derivatives bearing this unique combination showed antioxidant activity in a time- and dose-dependent manner, and also displayed different antiproliferative profiles in a panel of eight cancer cell lines as determined by the MTT assay. Ibuprofen derivative 5 was not only the most antioxidant agent, but also selectively induced toxicity in all the cancer cell lines tested (IC50 < 10 µM) while sparing nonmalignant cells, and induced apoptosis partially without enhancing the caspase 3/7 activity. Furthermore, NSAID derivative 5 significantly suppressed tumor growth in a subcutaneous colon cancer xenograft mouse model (10 mg/kg, TGI = 72%, and T/C = 38%) without exhibiting any apparent toxicity. To our knowledge, this work constitutes the first report on in vitro and in vivo anticancer activity of an unprecedented Se-NSAID hybrid derivative and its rational use for developing precursors for bioisosteric selenocompounds with appealing therapeutic applications.

We have carried out the design, synthesis, and evaluation of a small library of 2-aminobenzoxazole-appended coumarins as novel inhibitors of tumour-related CAs IX and XII. Substituents on C-3 and/or C-4 positions of the coumarin scaffold, and on the benzoxazole moiety, together with the length of the linker connecting both units were modified to obtain useful structure-activity relationships. CA inhibition studies revealed a good selectivity towards tumour-associated CAs IX and XII (Ki within the mid-nanomolar range in most of the cases) in comparison with CAs I, II, IV, and VII (Ki > 10 µM); CA IX was found to be slightly more sensitive towards structural changes. Docking calculations suggested that the coumarin scaffold might act as a prodrug, binding to the CAs in its hydrolysed form, which is in turn obtained due to the esterase activity of CAs. An increase of the tether length and of the substituents steric hindrance was found to be detrimental to in vitro antiproliferative activities. Incorporation of a chlorine atom on C-3 of the coumarin moiety achieved the strongest antiproliferative agent, with activities within the low micromolar range for the panel of tumour cell lines tested.

Cancer remains one of the diseases with the highest worldwide incidence. Several cytotoxic approaches have been used over the years to overcome this public health threat, such as chemotherapy, radiotherapy, and photodynamic therapy (PDT). Cyanine dyes are a class of compounds that have been extensively studied as PDT sensitisers; nevertheless, their antiproliferative potential in the absence of a light source has been scarcely explored. Herein, the synthesis of eighteen symmetric mono-, tri-, and heptamethine cyanine dyes and their evaluation as potential anticancer agents is described. The influences of the heterocyclic nature, counterion, and methine chain length on the antiproliferative effects and selectivities were analysed, and relevant structure–activity relationship data were gathered. The impact of light on the cytotoxic activity of the most promising dye was also assessed and discussed. Most of the monomethine and trimethine cyanine dyes under study demonstrated a high antiproliferative effect on human tumour cell lines of colorectal (Caco-2), breast (MCF-7), and prostate (PC-3) cancer at the initial screening (10 µM). However, concentration–viability curves showed higher potency and selectivity for the Caco-2 cell line. A monomethine cyanine dye derived from benzoxazole was the most promising compound (IC50 for Caco-2 = 0.67 µM and a selectivity index of 20.9 for Caco-2 versus normal human dermal fibroblasts (NHDF)) and led to Caco-2 cell cycle arrest at the G0/G1 phase. Complementary in silico studies predicted good intestinal absorption and oral bioavailability for this cyanine dye. [ABSTRACT FROM AUTHOR]

A series of new quinazolinones and related compounds has been conveniently synthesized via reaction of (E)-3-(1,3-diphenyl-1H-pyrazol-4-yl)-2-(6-iodo-4-oxo-4H-benzo[d] [1,3] oxazin-2-yl)acrylonitrile (2) with different nitrogen nucleophiles. The structures of the prepared compounds were fully elucidated using IR, 1H-NMR, and 13C-NMR spectra. The newly synthesized compounds were tested in vitro against a panel of three human tumor cell lines, namely, hepatocellular carcinoma (liver) HepG2, mammary gland breast MCF-7, and colon cancer HCT-116. Some of the tested compounds showed satisfactory activity. [ABSTRACT FROM AUTHOR]

Cancer remains one of the diseases with the highest worldwide incidence. Several cytotoxic approaches have been used over the years to overcome this public health threat, such as chemotherapy, radiotherapy, and photodynamic therapy (PDT). Cyanine dyes are a class of compounds that have been extensively studied as PDT sensitisers; nevertheless, their antiproliferative potential in the absence of a light source has been scarcely explored. Herein, the synthesis of eighteen symmetric mono-, tri-, and heptamethine cyanine dyes and their evaluation as potential anticancer agents is described. The influences of the heterocyclic nature, counterion, and methine chain length on the antiproliferative effects and selectivities were analysed, and relevant structure–activity relationship data were gathered. The impact of light on the cytotoxic activity of the most promising dye was also assessed and discussed. Most of the monomethine and trimethine cyanine dyes under study demonstrated a high antiproliferative effect on human tumour cell lines of colorectal (Caco-2), breast (MCF-7), and prostate (PC-3) cancer at the initial screening (10 µM). However, concentration–viability curves showed higher potency and selectivity for the Caco-2 cell line. A monomethine cyanine dye derived from benzoxazole was the most promising compound (IC50 for Caco-2 = 0.67 µM and a selectivity index of 20.9 for Caco-2 versus normal human dermal fibroblasts (NHDF)) and led to Caco-2 cell cycle arrest at the G0/G1 phase. Complementary in silico studies predicted good intestinal absorption and oral bioavailability for this cyanine dye.

A series of 1,3 and 1,4-bis[5-(R-sulfanyl)-1,2,4-triazol-3-yl)benzene derivatives were synthesized by the reaction of isophthalic and terephthalic acid hydrazides with methyl and aryl isothiocyanates, followed by base-catalyzed cyclization and alkylation of the resulting bis-triazolethiols with alkyl bromides. The suggested obesity–colorectal cancer association initiated evaluation of the antiproliferative activity of the newly synthesized compounds against a panel of obesity-related colorectal cells and inhibition of pancreatic lipase (PL). In vitro enzymatic, colorimetric, and cell culture bioassays were carried out with respective reference agents. Among the tested compounds, 1,3-bis{5-[(4-bromobenzyl)sulfanyl]-4-methyl-4H-1,2,4-triazol-3-yl}benzene showed clearly promising, though unselective, cytotoxicity in HT29, HCT116, SW620, CACO2, and SW480 cancer cells with a PL-IC50 value of 9.57±1.21 μM (<10 μM). Hence, the pharmacophores of most promising compounds can be druggable leads with a novel duality of antidiabesity–antineoplastic capacities and optimized potency and safety. Mechanistic examinations for hindrance of lipolysis catalysis and apoptogenic growth inhibition propensity may be attempted. [ABSTRACT FROM AUTHOR]

Buthina Abdallah Al-Oudat,1 Mohammad Ali Alqudah,2 Suaad Abdallah Audat,3 Qosay Ali Al-Balas,1 Tamam El-Elimat,1 Mohammad Abdelhafeez Hassan,1 Islam Nawaf Frhat,1 Marwah Mohammad Azaizeh2 1Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Jordan University of Science and Technology, Irbid 22110, Jordan; 2Department of Clinical Pharmacy, College of Pharmacy, Jordan University of Science and Technology, Irbid 22110, Jordan; 3Department of Chemistry, College of Science and Arts, Jordan University of Science and Technology, Irbid 22110, Jordan Background: Chrysin (5,7-dihydroxyflavone) is a widely distributed natural flavonoid found in many plant extracts, honey and propolis. Several studies revealed that chrysin possesses multiple biological activities including anti-cancer effects. It has been established that activation of apoptosis is the key molecular mechanism responsible for the cytotoxic potential of chrysin. The objective of this study was to design and synthesize potent chrysin analogues as potential cytotoxic agents.Methods: A series of chrysin derivatives (3a-m) bearing N'-alkylidene/arylideneacetohydrazide moiety were designed, synthesized, and evaluated for their antiproliferative activity against two human breast cancer cell lines, MDA-MB-231 and MCF-7 by applying the MTT colorimetric assay. Selected compounds were tested for their ability to induce apoptosis through caspase 3/7 activation in MDA-MB-231 cells only since MCF-7 cells lack procaspase 3.Results: Compounds (3a-m) were obtained as geometrical isomers (E/Z isomers) in good yields upon treatment of hydrazide 5 with different aliphatic and aromatic aldehydes. Most of the synthesized compounds demonstrated moderate-to-good activity against both cell lines. The cytotoxicity results revealed the importance of lipophilic moieties at C-4 position of ring D in imparting the cytotoxic activities to the compounds. Compound 3e with 4-benzyloxy substituent was found to be the most active among the synthesized compounds with IC50 3.3 µM against MDA-MB-231 and 4.2 µM against MCF-7 cell lines. The cytotoxic potential of compound 3e is comparable to that of the well-known anti-cancer agent doxorubicin. In addition, compounds substituted with fluoro (3b), nitro (3h), and dimethylamino (3j) exhibited good cytotoxicity with IC50

Thrombin is a serine protease that plays a crucial role in hemostasis, fibrinolysis, cell proliferation, and migration. Thrombin binding aptamer (TBA) is able to inhibit the activity of thrombin molecule via binding to its exosite I. This 15-nt DNA oligonucleotide forms an intramolecular, antiparallel G-quadruplex structure with a chair-like conformation. In this paper, we report on our investigations on the influence of certain modified nucleotide residues on thermodynamic stability, folding topology, and biological properties of TBA variants. In particular, the effect of single incorporation of a novel 4-thiouracil derivative of unlocked nucleic acid (UNA), as well as single incorporation of 4-thiouridine and all four canonical UNAs, was evaluated. The studies presented herein have shown that 4-thiouridine in RNA and UNA series, as well as all four canonical UNAs, can efficiently modulate G-quadruplex thermodynamic and biological stability, and that the effect is strongly position dependent. Interestingly, TBA variants containing the modified nucleotide residues are characterized by unchanged folding topology. Thrombin time assay revealed that incorporation of certain UNA residues may improve G-quadruplex anticoagulant properties. Noteworthy, some TBA variants, characterized by decreased ability to inhibit thrombin activity, possess significant antiproliferative properties reducing the viability of the HeLa cell line even by 95% at 10 μM concentration.

Several new (5-aryloxy-pyrazolyl)- and (5-aryl/olefin-sulfanyl-pyrazolyl)-dibenzo[b,e] [1,4] diazepinone scaffolds have been synthesized, by assembling 5-substituted 3-methyl-1-phenyl-pyrazole-4-carbaldehydes of varied nature with different cyclic diketones and aromatic diamines successfully in the presence of indium chloride in acetonitrile, at room temperature. Desired products are excellent in the purity and isolated without chromatography. All new structures are confirmed, on the basis of single-crystal X-ray diffraction data of representative 29e. Compounds reported in the present work revealed good antioxidant, antimicrobial and antiproliferative activities with promising FRAP (ferric reducing antioxidant power), bacterial resistance and human solid tumor cell growth inhibitory values, respectively. Compounds 25c and 29e, overall, registered good to moderate activity against A549 (lung), HeLa (cervix), SW1573 (lung) T-47D (breast) and WiDr (colon) cell lines, with GI50 values in the 2.6–5.1 μM and 1.8–7.5 μM ranges, respectively. Molecular docking was carried out to elucidate the binding modes of the compounds (25c, 29e) to topoisomerase I and II. [ABSTRACT FROM AUTHOR]

DNA is prone to structural polymorphism: beyond the iconic Watson-Crick double helix, nucleic acids can adopt a number of unusual motifs, at least in vitro. Scientists around the world gather every two years to discuss two of these oddities: G-quadruplexes and i-DNA. The seventh international meeting on G-quadruplex Nucleic Acids was held in Changchun, in Jilin province of the P.R. of China, approx. 1000 km North-east of Beijing. Nearly 320 participants gathered from Asia, Europe, North America and Oceania. More than 80 talks and as many posters summarized our current knowledge of these unusual DNA and RNA structures. During this meeting, the creation of the G4 society was announced, in order to coordinate efforts and share tools and knowledge in our field (https://www.g4-society.org). • Meeting report for the seventh International Meeting on Quadruplex Nucleic Acids, Changchun, China, 6–9 Sept 2019. • Over 300 scientists gathered to share their newest results in the Quadruplex field. • Recurrent themes were: structure and folding, applications to biotechnologies, formation in cells, proteins & ligands. [ABSTRACT FROM AUTHOR]

The synthesis and evaluation of small-molecule inhibitors of tubulin polymerization remains a promising approach for the development of new therapeutic agents for cancer treatment. The natural products colchicine and combretastatin A-4 (CA4) inspired significant drug discovery campaigns targeting the colchicine site located on the beta-subunit of the tubulin heterodimer, but so far these efforts have not yielded an approved drug for cancer treatment in human patients. Interest in the colchicine site was enhanced by the discovery that a subset of colchicine site agents demonstrated dual functionality as both potent antiproliferative agents and effective vascular disrupting agents (VDAs). Our previous studies led to the discovery and development of a 2-aryl-3-aroyl-indole analogue (OXi8006) that inhibited tubulin polymerization and demonstrated low nM IC 50 values against a variety of human cancer cell lines. A water-soluble phosphate prodrug salt (OXi8007), synthesized from OXi8006, displayed promising vascular disrupting activity in mouse models of cancer. To further extend structure-activity relationship correlations, a series of 6-aryl-3-aroyl-indole analogues was synthesized and evaluated for their inhibition of tubulin polymerization and cytotoxicity against human cancer cell lines. Several structurally diverse molecules in this small library were strong inhibitors of tubulin polymerization and of MCF-7 and MDA-MB-231 human breast cancer cells. One of the most promising analogues (KGP591) caused significant G2/M arrest of MDA-MB-231 cells, disrupted microtubule structure and cell morphology in MDA-MB-231 cells, and demonstrated significant inhibition of MDA-MB-231 cell migration in a wound healing (scratch) assay. A phosphate prodrug salt, KGP618, synthesized from its parent phenolic precursor, KGP591, demonstrated significant reduction in bioluminescence signal when evaluated in vivo against an orthotopic model of kidney cancer (RENCA-luc) in BALB/c mice, indicative of VDA efficacy. The most active compounds from this series offer promise as anticancer therapeutic agents. [Display omitted] • Synthesized 6-aryl-3-aroyl-indole analogues inspired by OXi8006 and sabizabulin. • Strong inhibition of tubulin polymerization (colchicine site) for best molecules. • Low-to-sub-μM tubulin activity generally correlated with low nM cytotoxicity. • Evaluation of KGP618 for vascular disruption in orthotopic RENCA mouse kidney tumor. • Inhibition of MDA-MB-231 breast cancer cell migration in scratch assay for KGP591. [ABSTRACT FROM AUTHOR]

A series of novel dihydroquinolin-4(1 H)-one derivatives targeting colchicine binding site on tubulin were designed, synthesized and evaluated as anticancer agents. The most potent compound 6t showed remarkable antiproliferative activities against four cancer cell lines with IC 50 values among 0.003–0.024 μM and tubulin polymerization inhibitory activity (IC 50 = 3.06 μM). Further mechanism studies revealed that compound 6t could induce K562 cells apoptosis and arrest at the G 2 /M phase. Meanwhile, 6t significantly inhibited migration and invasion of MDA-MB-231 cells, and disrupted the angiogenesis in human umbilical vein endothelial cells (HUVECs) in vitro. In addition, compound 6t inhibited tumor growth in H22 allograft tumor model with a tumor growth inhibition (TGI) rate of 63.3 % (i.v., 20 mg/kg per day) without obvious toxicity. Collectively, these results indicated that compound 6t was a novel tubulin polymerization inhibitor with potent anticancer properties in vitro and in vivo. [Display omitted] • • A series of dihydroquinolin-4(1 H)-one derivatives were designed and synthesized. • • Compound 6t showed the most antiproliferative potential against cancer cell lines. • • Compound 6t exhibited tubulin polymerization inhibition in vitro. • • 6t inhibited tumor growth in H22 allograft model by 63.3 % at a dose of 20 mg/kg. [ABSTRACT FROM AUTHOR]

Cancer is the world’s second leading cause of death, accounting for nearly 10 million deaths and 19.3 million new cases in 2020. Curcumin analogs are gaining popularity as anticancer agents currently. We reported herein the isolation, molecular engineering, molecular docking, antiproliferative, and anti-epidermal growth factor receptor (anti-EGFR) activities of curcumin analogs. Three curcumin analogs were prepared and docked against the epidermal growth factor receptor (EGFR), revealing efficient binding. Antiproliferative activity against 60 NCI cancer cell lines was assessed using National Cancer Institute (NCI US) protocols. The compound 3b,c demonstrated promising antiproliferative activity in single dose (at 10 µM) as well as five dose (0.01, 0.10, 1.00, 10, and 100 µM). Compound 3c inhibited leukemia cancer panel better than other cancer panels with growth inhibition of 50% (GI50) values ranging from 1.48 to 2.73 µM, and the most promising inhibition with GI50 of 1.25 µM was observed against leukemia cell line SR, while the least inhibition was found against non-small lung cancer cell line NCI-H226 with GI50 value of 7.29 µM. Compounds 3b,c demonstrated superior antiproliferative activity than curcumin and gefitinib. In molecular docking, compound 3c had the most significant interaction with four H-bonds and three π–π stacking, and compound 3c was found to moderately inhibit EGFR. The curcumin analogs discovered in this study have the potential to accelerate the anticancer drug discovery program.

Brain tumor, as any type of cancer, is assumed to be sustained by a small subpopulation of stem-like cells with distinctive properties that allow them to survive conventional therapies and drive tumor recurrence. Thus, the identification of new molecules capable of controlling stemness properties may be key in developing effective therapeutic strategies for cancer by inducing stem-like cells differentiation. Spiropyrazoline oxindoles have previously been shown to induce apoptosis and cell cycle arrest, as well as upregulate p53 steady-state levels, while decreasing its main inhibitor MDM2 in the HCT116 human colorectal carcinoma cell line. In this study, we made modifications in this scaffold by including combinations of different substituents in the pyrazoline ring in order to obtain novel small molecules that could modulate p53 activity and act as differentiation inducer agents. The antiproliferative activity of the synthesized compounds was assessed using the isogenic pair of HCT116 cell lines differing in the presence or absence of the p53 gene. Among the tested spirooxindoles, spiropyrazoline oxindole 1a was selective against the cancer cell line expressing wild-type p53 and presented low cytotoxicity. This small molecule induced neural stem cell (NSC) differentiation through reduced SOX2 (marker of multipotency) and increased βIII-tubulin (marker of neural differentiation) which suggests a great potential as a non-toxic inducer of cell differentiation. More importantly, in glioma cancer cells (GL-261), compound 1a reduced stemness, by decreasing SOX2 protein levels, while also promoting chemotherapy sensitization. These results highlight the potential of p53 modulators for brain cell differentiation, with spirooxindole 1a representing a promising lead molecule for the development of new brain antitumor drugs.

Plain language summary Pyrazolo[3,4- d ]pyrimidines are chemical compounds possessing remarkable versatility and significance in both biological and chemical contexts. These compounds are composed of specific arrangements of atoms, forming a unique ring structure, which is able to form bonds in a similar way as purines do. In the realm of chemistry, pyrazolo[3,4- d ]pyrimidines showcase impressive flexibility due to their ability to easily react with various molecules, opening avenues for the creation of novel compounds with diverse properties for potential applications in medicinal chemistry. In a biological context, pyrazolo[3,4- d ]pyrimidines play a crucial role due to their interaction with proteins such as enzymes. In fact, these compounds can impact various biological processes, including cancer cell proliferation, oxidative stress and inflammation. This has led to investigations into their potential as therapeutic agents: by designing pyrazolo[3,4- d ]pyrimidines with specific biological targets in mind, new drugs can be developed for the effective treatment of a range of medical conditions. Finally, novel administration tools (e.g., nanomaterials and functionalized liposomes) are being studied as effective ways to overcome the main unwanted characteristics of pyrazolo[3,4- d ]pyrimidines (scarce solubility and off-target side effects), thereby increasing their efficacy and specificity toward cell targets. In conclusion, pyrazolo[3,4- d ]pyrimidines are fascinating molecules with a dual role in chemistry and biology. Their adaptability in chemical reactions makes them valuable building blocks for designing new compounds with diverse applications. Additionally, their interaction with biological molecules holds promise for the development of innovative medicines. Ongoing research into the properties and behaviors of these compounds could lead to significant advancements in both scientific fields.

Diterpenoid alkaloids with remarkable chemical properties and biological activities are frequently found in plants of the genera Aconitum, Delphinium, and Garrya. However, little information has been reported on the antiproliferative effects of the diterpenoid alkaloid constituents of Aconitum and Delphinium plants. C-1 and 14 esterifications of delcosine (1) were carried out to provide 39 new diterpenoid alkaloid derivatives (3–14, 16–29, 3a–7a, 9a, 13a, 13b, 14a, 14b, 16a, 17a, 24a, 35a). Selected compounds (3–14, 16–29, 3a–7a, 9a, 13a, 13b, 14a, 14b, 16a, 17a, 24a, 35a) were evaluated for antiproliferative activity against three to five human tumor cell lines including triple-negative breast cancer (TNBC) and P-glycoprotein (P-gp) overexpressing multidrug-resistant (MDR) subline. Several newly synthesized delcosine derivatives (6, 7, 13, 13a, 13b) showed substantial suppressive effects against all human tumor cell lines tested. In contrast, the natural alkaloids (1, 31, 33) showed no effect. Most of the active compounds were delcosine derivatives with two specific substitution patterns—C-1 and C-1,14. In particular, 1-acyldelcosine derivative (5–7) displayed more potency than 1,14-diacyldelcosine derivatives (5a–7a). These acylated alkaloid derivatives caused accumulation of TNBC cells at sub-G1 within 24 h. 1-Acylation of 1 appears to be critical for producing antiproliferative activity in this alkaloid class and a means to provide promising new leads for further development into antitumor agents. [ABSTRACT FROM AUTHOR]

Copyright of Boletín Latinoamericano y del Caribe de Plantas Medicinales y Aromáticas is the property of Universidad de Santiago de Chile and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Graphical abstract Highlights • Antiproliferative 3-deaoxysphingomyelin analogs were developed. • Cytotoxicity evaluation against cell lines representing four major types of cancers. • Alkyl chain influence the activity more than pyrrolidine ring stereochemistry. • Concentration dependent mechanism of action for this class of compounds. • Akt phorphorylation inhibition might be the mechanism of action at low concentration. Abstract Sphingomyelins and glycerophospholipids are structurally related phospholipids. Nevertheless, glycerophospholipids analogs are known as antitumor agents while sphingomyelin analogs were reported as cytoprotective agents. Herein, we have addressed the development of 3-deoxysphingomyelin analogs as cytotoxic agents possessing modified sphingobases. Thus, pyrrolidine-based 3-deoxysphingomyelin analogs were synthesized and evaluated against a panel of cell lines representing four major types of cancers. Compounds 3d , 4d and 6d elicited better GI 50 values than the FDA approved drug miltefosine. Investigation of their impact on Akt phosphorylation as a possible mechanism for the antiproliferative activity of this class of compounds revealed that these compounds might elicit a concentration-dependent mechanism via inhibition of Akt phosphorylation at the lower concentration. Molecular docking predicted their binding modes to Akt to involve polar head binding to the Pleckstrin homology domain and hydrophobic tail extension into a hydrophobic pocket connecting the Pleckstrin homology domain and the kinase domain. As a whole, the described work suggests compounds 3d , 4d and 6d as promising pyrrolidine-based 3-deoxysphingomyelin analogs for development of novel cancer therapies. [ABSTRACT FROM AUTHOR]

Pyrimido-pyrimidine derivatives have been developed as rigid merbarone analogues. In a previous study, these compounds showed potent antiproliferative activity and efficiently inhibited topoisomerase IIα. To further extend the structure–activity relationships on pyrimido-pyrimidines, a novel series of analogues was synthesized by a two-step procedure. Analogues 3–6 bear small alky groups at positions 1 and 3 of the pyrimido-pyrimidine scaffold whereas at position 6a (4-chloro)phenyl substituent was inserted. The basic side chains introduced at position 7 were selected on the basis of the previously developed structure–activity relationships. The antiproliferative activity of the novel compounds proved to be affected by both the nature of the basic side chain and the substituents on the pyrimido-pyrimidine moiety. Derivatives 5d and 5e were identified as the most promising molecules still showing reduced antiproliferative activity in comparison with the previously prepared pyrimido-pyrimidine analogues. In topoisomerase IIα-5d docking complex, the ligand would poorly interact with the enzyme and assume a different orientation in comparison with 1d bioactive conformation.

Cancer is a leading cause of death worldwide. Multidrug resistance (MDR) is a main reason of chemotherapy failure in many patients and is often related to overexpression of ATP-binding cassette (ABC) transporters, including P-glycoprotein (P-gp/ABCB1). Agents that are capable of modulation of the activity of these transporters might be effective in overcoming MDR. In this study, a new set of 1,4,5,6,7,8-hexahydro 5-oxo quinoline-3-carboxamide derivatives bearing 4-methylthiazole moiety and their tetrahydroquinoline counterparts were synthesized. MDR reversal activity of these 16 newly synthesized derivatives was tested in P-gp overexpressing MES-SA-DX5 human uterine sarcoma cells by flow cytometric determination of Rhodamine123 efflux. The effect of the most potent compounds in induction of apoptosis and alterations of cell cycle was examined in these cells by a flow cytometric method. Inherent cytotoxicity of the synthesized compounds was evaluated against MCF-7, A-549 and K562 cancer cell lines, as well as MES-SA-DX5 and their parental non-resistant MES-SA and also HEK-293 non-cancerous cells by MTT assay. Compounds A1 and A2 with 5-oxo-hexahydroquinoline structure bearing 2,4-dichlorophenyl and 4-bromophenyl moieties, respectively, and their tetrahydroquinoline counterparts B1 and B2 significantly blocked P-gp efflux, induced apoptosis and showed the highest cytotoxicities against MES-SA-DX5 cells. However, only A2 and B2 compounds were relatively selective against cancer and MDR cells as compared to non-resistant and non-cancerous cells. These findings demonstrate that 5-oxo-hexahydroquinoline and 5-oxo-tetrahydroquinoline derivatives represent promising agents with therapeutic potential in drug resistant cancers.

The present work aims to design and synthesize novel series of spiro pyrazole-3,3’-oxindoles analogues and investigate their bioactivity as antioxidant and antimicrobial agents, as well as antiproliferative potency against selected human cancerous cell lines (i.e., breast, MCF-7; colon, HCT-116 and liver, HepG-2) relative to healthy noncancerous control skin fibroblast cells (BJ-1). The mechanism of their cytotoxic activity has been also examined by immunoassaying the levels of key anti- and proapoptotic protein markers. The analytical and spectral data of the all synthesized target congeners were compatible with their structures. Synthesized compounds showed diverse moderate to powerful antimicrobial and antioxidant activities. Results of MTT assay revealed that seven synthesized compounds (i.e., 11a, 11b, 12a, 12b, 13b, 13c and 13h) particularly exhibited significant cytotoxicity against the three cancerous cell lines under investigation. Ranges of IC50 values obtained were 5.7−21.3 and 5.8−37.4 µg/mL against HCT-116 and MCF-7, respectively; which is 3.8 and 6.5-fold (based on the least IC50 values) more significant relative to the reference chemotherapeutic drug doxorubicin. In HepG-2 cells, the analogue 13h exhibited the highest cytotoxicity with IC50 value of 19.2µg/mL relative to doxorubicin (IC50 = 21.6µg/mL). The observed cytotoxicity was specific to cancerous cells, as evidenced by the minimal toxicity in the noncancerous control skin-fibroblast cells. ELISA results indicated that the observed antiproliferative effect against examined cancer cell lines is mediated via engaging the activation of apoptosis as illustrated by the significant increase in proapoptotic protein markers (p53, bax and caspase-3) and reduction in the antiapoptotic marker bcl-2. Taken together, results of the present study emphasize the potential of spiro pyrazole-oxindole analogues as valuable candidate anticancer agents against human cancer cells.

A series of phenylbipyridinylpyrazoles was synthesized through the reaction of 2-(4-(2-chloropyridin-4-yl)-3-(3-methoxy-5-methylphenyl)-1H-pyrazol-1-yl)acetonitrile (4) with different 6-substituted pyridine-3-ylboronic acids. The final compounds 5a–j were screened at 10 µM against over 60 tumor cell lines at the U.S. National Cancer Institute (NCI). In light of the NCI results, compounds 5c and 5h showed a broad spectrum of activity against NCI cell lines with mean growth of 53% and 58%, respectively. Compound 5e behaved differently as it showed high degree of selectivity and potency by inhibiting 96% of growth of leukemia SR cell line at 10 µM. Standard COMPARE analyses were performed at the GI50 level and the results exhibit high correlation in the form of pairwise correlation coefficient (PCC) of more than 0.6 between three of the current compounds and three standard known anticancer agents. Compound 5e demonstrated high correlation levels with merbarone (NSC S336628) with a PCC value of 0.631. Compound 5h showed a considerably high PCC value of 0.626 with dichloroallyl lawsone, while compound 5i, showed PCC values of 0.601 and 0.604 with both dichloroallyl lawsone and N,N-dibenzyldaunomycin (NSC S268242), respectively. These three standard agents have anticancer activity via two major mechanism of actions, inhibition of topoisomerase II and inhibition of biosynthesis of pyrimidine nucleotides, therefore, compounds 5a–j are promising therapeutic agents for targeting different human malignancies. Prediction of drug-likeness and toxicity of these newly synthesized derivatives were also considered.

Six new cyclodiprenyl phenols were synthesized by direct coupling of perillyl alcohol and the appropriate phenol. Their structures were established by IR, HRMS and mainly NMR. Three human cancer cell lines--breast (MCF-7), prostate (PC-3) and colon (HT-29)--were used in antiproliferative assays, with daunorubicin and dunnione as positive controls. Results described in the article suggest that dihydroxylated compounds 2-4 and monohydroxylated compound 5 display selectivity against cancer cell lines, cytotoxicity, apoptosis induction, and mitochondrial membrane impairment capacity. Compound 2 was identified as the most effective of the series by displaying against all cancer cell lines a cytotoxicity close to dunnione antineoplastic agent, suggesting that the cyclodiprenyl phenols from perillyl alcohol deserve more extensive investigation of their potential medicinal applications. [ABSTRACT FROM AUTHOR]

Abstract: The series of new hydrazide derivatives were synthesized in reactions of N3-substituted amidrazones with cyclic anhydrides as potential anti-inflammatory and antibacterial agents. The compounds were characterized by 1H-13C two-dimensional NMR techniques, which revealed the presence of two tautomeric forms in DMSO-d6 solutions, while the molecular structure of one species was confirmed by single-crystal X-ray diffraction. The anti-inflammatory effects of hydrazides on peripheral blood mononuclear cells were experimentally evaluated. Three compounds showed antiproliferative activity comparable to ibuprofen. One derivative demonstrated strong reduction of lymphocyte proliferation stimulated by anti-CD3 antibody (by 90%) and PHA, as well as low cell toxicity. The obtained compounds exhibited relatively weak antibacterial activity; they were more effective against Gram-positive bacterial strains.Graphical abstract: [ABSTRACT FROM AUTHOR]

Abstract: Reactions of dicobalt octacarbonyl [Co2(CO)8] with 2′‐deoxy‐5‐oxopropynyluridines and related compounds gave dicobalt hexacarbonyl nucleoside complexes (83–31 %). The synthetic outcomes were confirmed by X‐ray structure determination of dicobalt hexacarbonyl 2′‐deoxy‐5‐(4‐hydroxybut‐1‐yn‐1‐yl)uridine, which exhibits intermolecular hydrogen bonding between a modified base and ribose. The electronic structure of this compound was characterized by the DFT calculations. The growth inhibition of HeLa and K562 cancer cell lines by organometallic nucleosides was examined and compared to that by alkynyl nucleoside precursors. Coordination of the dicobalt carbonyl moiety to the 2′‐deoxy‐5‐alkynyluridines led to a significant increase in the cytotoxic potency. The cobalt compounds displayed antiproliferative activities with median inhibitory values (IC50) in the range of 20 to 80 μ m for the HeLa cell line and 18 to 30 μ m for the K562 cell line. Coordination of an acetyl‐substituted cobalt nucleoside was expanded by using the 1,1‐bis(diphenylphosphino)methane (dppm) ligand, which exhibited cytotoxicity at comparable levels. The formation of reactive oxygen species in the presence of cobalt compounds was determined in K562 cells. The results indicate that the mechanism of action for most antiproliferative cobalt compounds may be related to the induction of oxidative stress. [ABSTRACT FROM AUTHOR]

Microtubules are recognized as crucial components of the mitotic spindle during cell division, and, for this reason, the microtubule system is an attractive target for the development of anticancer agents. Continuing our search strategy for novel tubulin targeting-compounds, a new series of 2-alkoxycarbonyl-3-(3′,4′,5′-trimethoxyanilino)-5-aryl/heteroarylthiophene derivatives was designed, synthesized and demonstrated to act as tubulin polymerization inhibitors at the colchicine site. A structure-activity relationship study on the phenyl at the 5-position of the thiophene ring was performed by introducing a variety of substituents containing electron-releasing and electron-withdrawing groups, with the 2-alkoxycarbonyl-3-(3′,4′,5′-trimethoxyanilino)thiophene scaffold being the minimum structural requirement for activity. Of the tested compounds, derivatives 4a , 4c , 4i and 4k possessed the highest overall potency and displayed high antiproliferative activities at submicromolar concentrations, with IC 50 values ranging from 0.13 to 0.84 μM against four different cancer cell lines. Three agents ( 4a , 4c and 4i ) in the present series had similar effects, and these were comparable to those of the reference compound combretastatin A-4 (CA-4) as inhibitors of tubulin assembly. The antitubulin effects correlated with the cytostatic activities and indicate that these compounds inhibit cell growth through inhibition of tubulin polymerization by binding at the colchicine site. Compound 4c , containing the 2′-thienyl ring at the 5-position of the 2-methoxycarbonyl-3-(3′,4′,5′-trimethoxyanilino)thiophene scaffold, exhibited substantial antiproliferative activity with a mean IC 50 value of 140 nM, inhibited tubulin polymerization with an IC 50 value of 1.2 μM, similar to that of CA-4 (IC 50 : 1.1 μM), and induced apoptosis in HeLa cells. [ABSTRACT FROM AUTHOR]

Human choline kinase is a well validated target for the treatment of cancer. In the last two decades, many choline kinase inhibitors have been developed and one of them is currently under evaluation in clinical trials. In this paper a series of 6-(benzylthio)-9 H-purin-9-yl-pyridinium derivatives were evaluated as choline kinase inhibitors, and their effects on cell proliferation were also investigated in the human hepatoma HepG2 cell line. The most potent inhibitor against purified choline kinase-α1 presents an IC value of 0.4 μM. The biological data and the docking studies described here, support that the 4-(dimethylamino)pyridinium cationic head and a small linker (benzene or biphenyl) are the essential structural parameters for choline kinase inhibition of the tested compounds. [ABSTRACT FROM AUTHOR]