Synthesis and biological evaluation of indolyl chalcones as antitumor agents

A series of indolyl chalcones were synthesized and evaluated in vitro for their anticancer activity against three human cancer cell lines. Compounds 3b–d, 3h, 3j, 3l, 3m, 4g, and 4j showed significant cytotoxicity, particularly, indolyl chalcones 3l and 3m were identified as the most potent and selective anticancer agents with IC₅₀ values 0.03 and 0.09 μM, against PaCa-2 cell line, respectively.     

Synthesis of novel 3,5-diaryl pyrazole derivatives using combinatorial chemistry as inhibitors of tyrosinase as well as potent anticancer,anti-inflammatory agents

In the present article, we have synthesized a combinatorial library of 3,5-diaryl pyrazole derivatives using 8-(2-(hydroxymethyl)-1-methylpyrrolidin-3-yl)-5,7-dimethoxy-2-phenyl-4H-chromen-4-one (1) and hydrazine hydrate in absolute ethyl alcohol under the refluxed conditions. The structures of the compounds were established by IR, ¹H NMR and mass spectral analysis. All the synthesized compounds were evaluated for their anticancer activity against five cell lines (breast cancer cell line, prostate cancer cell line, promyelocytic leukemia cell line, lung cancer cell line, colon cancer cell line) and anti-inflammatory activity against TNF-α and IL-6. Out of 15 compounds screened, 2a and 2d exhibited promising anticancer activity (61–73% at 10 μM concentration) against all selected cell lines and IL-6 inhibition (47% and 42% at 10 μM concentration) as in comparison to standard flavopiridol (72–87% inhibition at 0.5 μM) and dexamethasone (85% inhibition at 1 μM concentration), respectively. Cytotoxicity of the compounds checked using CCK-8 cell lines and found to be nontoxic to slightly toxic. Out of 15, four 3,5-diaryl pyrazole derivatives exhibiting potent inhibitory activities against both the monophenolase and diphenolase actions of tyrosinase. The IC₅₀ values of compounds (2a, 2d, 2h and 2l) for monophenolase inhibition were determined to range between 1.5 and 30 μM. Compounds 2a, 2d, 2h and 2l also inhibited diphenolase significantly with IC₅₀ values of 29.4, 21.5, 2.84 and 19.6 μM, respectively. All four 3,5-diaryl pyrazole derivatives were active as tyrosinase inhibitors (2a, 2d, 2h and 2l), and belonging to competitive inhibitors. Interestingly, they all manifested simple reversible slow-binding inhibition against diphenolase.     

Antitumor agents 273. Design and synthesis of N-alkyl-thiocolchicinoids as potential antitumor agents

As a part of our continuing study of colchicinoids as therapeutically useful antitumor drugs, thiocolchicine derivatives, including their phosphate and other water soluble salts, were synthesized and evaluated for inhibition of tubulin polymerization and for in vitro cytotoxicity. Three compounds, 7, 10, and 11, showed potent inhibition of tubulin assembly (IC₅₀ = 0.88–1.1 μM). In addition, compound 7, a water soluble succinic acid salt of N-deacetylthiocolchicine (4), showed potent cytotoxicity against a panel of tumor cell lines, suggesting it might be a potential lead to be developed as a therapeutic antitumor agent. Compound 8, a water soluble succinic acid salt of N,N-dimethyl-N-deacetylthiocolchicine (5), showed selective activities against HCT-8 and SK-BR-3 cells. N,N-Diethyl-N-deacetylthiocolchicine (6) seemed not to be a substrate for the P-gp efflux pump, based on the similar ED₅₀ values obtained against P-gp over-expressing KBvin (0.0146 μg/mL) cells and the parent KB (0.0200 μg/mL) cell line.     

Antitumor agents 278. 4-Amino-2H-benzo[h]chromen-2-one (ABO) analogs as potent in vitro anti-cancer agents

4-Amino-2H-benzo[h]chromen-2-one (ABO) analogs were designed, synthesized, and evaluated for cytotoxic activity. Among all 4-substituted ABO analogs, cyclohexyl (12), N-methoxy-N-methylacetamide (14), and various aromatic derivatives (15–25 and 27) exhibited promising cell growth inhibitory activity with ED₅₀ values of 0.01–5.8 μM against all tested tumor cell lines. The 4′-methoxyphenyl derivative (18) and 3′-methylphenyl derivative (24) showed the most potent antitumor activity against a broad range of cancer cell lines with ED₅₀ values of 0.01–76 μM. Preliminary SAR results indicated that substitutions on nitrogen are critical to the antitumor potency.     

3-Substituted-4-hydroxycoumarin as a new scaffold with potent CDK inhibition and promising anticancer effect: Synthesis,molecular modeling and QSAR studies

A new series of 3-substituted-4-hydroxycoumarin derivatives was designed, synthesized, and evaluated for CDK inhibiting and anticancer activities. All the synthesized target compounds showed remarkably high affinity and selectivity towards CDK1B, compared to flavopiridol, with Ki values in the low nanomolar range (Ki = 0.35–0.88 nM). Most of them elicited considerable inhibiting effect against CDK9T1 (Ki = 3.26–23.45 nM). Moreover, all the target compounds were tested in vitro against eighteen types of human tumor cell lines. The hydrazone 3a, N-phenylpyrazoline derivative 6b and 2-aminopyridyl-3-carbonitrile derivative 8c were the most potent anticancer agents against MCF-7 breast cancer cell line (IC₅₀ = 0.21, 0.21 and 0.23 nM, respectively). The target compounds 3a, 6b and 8c were further evaluated in MCF-7 breast cancer mouse xenograft model and showed in vivo efficacy at 10 mg/kg dose. The docking study confirmed a unique binding mode in the active site of CDK1B with better score than flavopiridol. Quantitative structure activity relationship study was done and revealed a highly predictive power R² of 0.81.     

Synthesis and anti-proliferative activity of aromatic substituted 5-((1-benzyl-1H-indol-3-yl)methylene)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione analogs against human tumor cell lines

Based on previous SAR studies on N-benzylindole and barbituric acid hybrid molecules, we have synthesized a series of aromatic substituted 5-((1-benzyl-1H-indol-3-yl)methylene)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione analogs (3a–i) and evaluated them for their in vitro growth inhibition and cytotoxicity against a panel of 60 human tumor cell lines. Compounds 3c, 3d, 3f and 3g were identified as highly potent anti-proliferative compounds against ovarian, renal and breast cancer cell lines with GI₅₀ values in low the nanomolar range. The 4-methoxy-N-benzyl analog (3d) was the most active compound with GI₅₀ values of 20 nM and 40 nM against OVCAR-5 ovarian cancer cells and MDA-MB-468 breast cancer cells, respectively. Two other analogs, 3c (the 4-methyl-N-benzyl analog) and 3g (the 4-fluoro-N-benzyl analog) exhibited equimolar potency against MDA-MB-468 cells GI₅₀ = 30 nM). Analog 3f (the 4-chloro-N-benzyl analog) exhibited a GI₅₀ value of 40 nM against renal cancer cell line A498. These results suggest that aromatic substituted N-benzylindole dimethylbarbituric acid hybrids may have potential for development as clinical candidates to treat a variety of solid tumors.     

Design,synthesis and biological activities of sorafenib derivatives as antitumor agents

A series of novel sorafenib derivatives, 9a–w, was designed and synthesized in high yields using various substituted anilines, and their antiproliferative activities against HCT116, PC-3 and MDA-MB-231 cell lines were also evaluated and described. All compounds exhibited potent antiproliferative activity against HCT116 and PC-3 cells with IC₅₀ = 2.8–52.0 and 2.2–45.6 μM; compounds 9p and 9q demonstrated competitive antiproliferative activities to sorafenib against all three cancer cell lines, the cytotoxicity of compound 9r is more potent than that of sorafenib. Compounds (9g, 9p, 9q and 9r) were chosen for further evaluation of the anti-angiogenesis activity, and showed the inhibition of sprout formation from aortic ring ex vivo. The structures of all the newly synthesized compounds were determined by ¹H NMR, ¹³C NMR and HRMS.     

Synthesis of new chromeno-annulated cis-fused pyrano[4,3-c]isoxazole derivatives via intramolecular nitrone cycloaddition and their cytotoxicity evaluation

New cis-fused chromeno pyrano[4,3-c]isoxazole derivatives have been synthesized by intramolecular [1,3]-cycloaddition of the nitrones generated in situ from hydroxylamine derivatives and 7-O-prenyl derivatives of 8-formyl-2,3-disubstituted chromenones using PEG-400 as a reaction medium under catalyst-free conditions good to excellent yields. The structures were established by spectroscopic data and further confirmed by X-ray diffraction analysis. The results showed that compounds 4b, 4c, 4d, 4e and 4k exhibit very potent antiproliferative activity against MDA-MB-231 breast cancer cells. Compounds 4a, 4c, 4e, 4i and 4k displayed potent inhibitory activity against human MCF-7 breast cancer cell lines. Compounds 4h and 4i exhibited significant anti-proliferative activity against human cervical cancer cell line, HeLa. While 4b, 4d and 4j were active against human lung cancer cell line, A549. In addition, Compound 4j was found to be the most promising against A549 (Lung cancer) with IC₅₀ value of 0.194 μM.     

Design,synthesis, in silico and in vitro studies of novel 4-methylthiazole-5-carboxylic acid derivatives as potent anti-cancer agents

Since inhibitors of mucin onco proteins are potential targets for breast cancer therapy, a series of novel 4-methylthiazole-5-carboxylic acid (1) derivatives 3a–k were synthesized by the reaction of 1 with SOCl₂ followed by different bases/alcohols in the presence of triethylamine. Once synthesized and characterized, their binding modes with MUC1 were studied by molecular docking analysis using Aruglab 4.0.1 and QSAR properties were determined using HyperChem. All synthesized compounds were screened for in vitro anti-breast cancer activity against MDA-MB-231 breast adenocarcinoma cell lines by Trypan-blue cell viability assay and MTT methods. Compounds 1, 3b, 3d, 3e, 3i and 3f showed good anti-breast cancer activity. Since 1 and 3d exhibited high potent activity against MDA-MB-231 cell lines, they show could be effective mucin onco protein inhibitors.     

Investigation of fluorinated and bifunctionalized 3-phenylchroman-4-one (isoflavanone) aromatase inhibitors

Fluorinated isoflavanones and bifunctionalized isoflavanones were synthesized through a one-step gold(I)-catalyzed annulation reaction. These compounds were evaluated for their in vitro inhibitory activities against aromatase in a fluorescence-based enzymatic assay. Selected compounds were tested for their anti-proliferative effects on human breast cancer cell line MCF-7. Compounds 6-methoxy-3-(pyridin-3-yl)chroman-4-one (3c) and 6-fluoro-3-(pyridin-3-yl)chroman-4-one (3e) were identified as the most potent aromatase inhibitors with IC₅₀ values of 2.5 μM and 0.8 μM. Therefore, these compounds have great potential for the development of pharmaceutical agents against breast cancer.     

Synthesis and biological evaluation of 2-phenol-4-chlorophenyl-6-aryl pyridines as topoisomerase II inhibitors and cytotoxic agents

A new series of 2-phenol-4-chlorophenyl-6-aryl pyridines were designed, synthesized, and evaluated for topoisomerase (topo) I and II inhibitory activities as well as cytotoxic activity against four different human cancer cell lines such as HCT15, T47D, DU145, and Hela. Most of the tested compounds exhibited stronger topo II inhibitory activity at 100 μM as compared to etoposide. All the compounds, except 39, did not show topo I inhibitory activity. Interestingly, compounds that showed better topo II inhibition than etoposide have ortho- or para-chlorophenyl at 4-position of central pyridine, and none of the compounds possess meta-chlorophenyl. SAR study revealed the importance of ortho- or para-chlorophenyl at 4-position of the central pyridine for selective topo II inhibitory activity. Similarly, all compounds possessing meta- or para-hydroxyphenyl moieties showed moderate to significant cytotoxic effects. Particularly, compounds 27–37, and 39 which showed excellent cytotoxicity (IC₅₀ = 0.68–1.25 μM) against T47D breast cancer cells suggest the importance of meta- or para-hydroxyphenyl moiety at 2-position of the central pyridine for the design of anticancer agents with related scaffolds.     

Facile synthesis of novel substituted aryl-thiazole (SAT) analogs via one-pot multi-component reaction as potent cytotoxic agents against cancer cell lines

In this study, twenty-five (25) substituted aryl thiazoles (SAT) 1–25 were synthesized, and their in vitro cytotoxicity was evaluated against four cancer cell lines, MCF-7 (ER^+ve breast), MDA-MB-231 (ER^−ve breast), HCT116 (colorectal) and HeLa (cervical). The activity was compared with the standard anticancer drug doxorubicin (IC₅₀ = 1.56 ± 0.05 μM). Among them, compounds 1, 4–8, and 19 were found to be toxic to all four cancer cell lines (IC₅₀ values 5.37 ± 0.56–46.72 ± 1.80 μM). Compound 20 was selectively active against MCF7 breast cancer cells with IC₅₀ of 40.21 ± 4.15 μM, whereas compound 19 was active against MCF7 and HeLa cells with IC₅₀ of 46.72 ± 1.8, and 19.86 ± 0.11 μM, respectively. These results suggest that substituted aryl thiazoles 1 and 4 deserve to be further investigated in vivo as anticancer leads.     

5-((1-Aroyl-1H-indol-3-yl)methylene)-2-thioxodihydropyrimidine-4,6(1H,5H)-diones as potential anticancer agents with anti-inflammatory properties

A series of novel 5-((1-aroyl-1H-indol-3-yl)methylene)-2-thioxodihydropyrimidine-4,6(1H,5H)-diones (3a–z) have been evaluated for in vitro cytotoxicity against a panel of 60 human tumor cell lines. Compound 3k exhibited the most potent growth inhibition against melanoma MDA-MB-435 cells (GI₅₀ = 850 nM), against leukemia SR cancer cells (GI₅₀ = 1.45 μM), and OVCAR-3 (GI₅₀ = 1.26 μM) ovarian cancer cell lines. The structurally related compound 3s had a GI₅₀ value of 1.77 μM against MDA-MB-435 cells. The N-naphthoyl analogue 3t had GI₅₀ values of 1.30 and 1.91 μM against HOP-92 non-small cell lung cancer and MDA-MB-435 melanoma cell lines, respectively. The related analogue 3w had GI₅₀ values of 1.09 μM against HOP-92 non-small cell lung cancer cell lines. Interestingly, docking of the two active molecules 3k and 3w into the active site of COX-2 indicates that these compounds are COX-2 ligands with strong hydrophobic and hydrogen bonding interactions. Thus, compounds 3k, 3t, 3s, and 3w constitute a new class of anticancer/anti-inflammatory agents that may have unique potential for cancer therapy.     

New antitumoral agents I: In vitro anticancer activity and in vivo acute toxicity of synthetic 1,5-bis(4-hydroxy-3-methoxyphenyl)-1,4-pentadien-3-one and derivatives

This paper describes a new method for the preparation of 1,5-bis(4-hydroxy-3-methoxyphenyl)-1,4-pentadien-3-one 1 and its derivatives 2–5. This set of synthetic compounds exhibited high antitumoral activities regarding in vitro screening against several human tumor cell lines as lung carcinoma NCI-460, melanoma UACC-62, breast MCF-7, colon HT-29, renal 786-O, ovarian OVCAR-03 and ovarian expressing the resistance phenotype for adriamycin NCI-ADR/RES, prostate PC-3, and leukemia K-562. Compounds were also tested against murine tumor cell line B16F10 melanoma and lymphocytic leukemia L1210 as well as to their effect toward normal macrophages. Specific activity against colon cancer cells HT-29 was observed for all tested compounds and suggests further studies with models of colon cancer. Compounds 1, 2, and 4 showed significant cytotoxic activity with IC₅₀ values ?2.3 μM for all human cancer cell lines. Intraperitoneal acute administration of compound 1 and 2 showed very low toxicity rate.     

Methylsulfonyl benzothiazoles (MSBT) derivatives: Search for new potential antimicrobial and anticancer agents

A series of novel 4 and 5-substituted methylsulfonyl benzothiazole (MSBT) compounds having amide, alkoxy, sulfonamide, nitro and amine functionality were synthesized from sequential reactions on 5-ethoxy-2-(methylsulfonyl)benzo[d]thiazole such as nitration, reduction, sulfonation, dealkylation, etc. All synthesized compounds were screened against antimicrobial and selected screened for anticancer activity. Antimicrobial activities studies reveled that among all compounds screened, out of MSBT-07, MSBT-11, MSBT-12, MSBT-14, MSBT-19, and MSBT-27 were found to have promising antimicrobial activity at MIC range of 4–50 μg/ml against selected bacterial as well as fungal species. Compounds having good antimicrobial activity were screened for cervical cancer (HeLA cell lines). Of these MSBT-07 and MSBT-12 significantly reduced the cell growth. Consequently their calculated GI₅₀ values were found to be 0.1 or <0.1 μM.     

Synthesis and anti breast cancer activity of biphenyl based chalcones

A series of (2E,2′E)-1,1′-(3-hydroxy-5-methylbiphenyl-2,6-diyl)-bis(3-pheylprop-2-ene-1-ones (5–33) were prepared by the reaction of 1,3-diacetyl biphenyls (1–4) with different aldehydes in presence of catalytic amount of solid KOH in ethanol in excellent yields. The compounds were evaluated for anticancer activity against human breast cancer MCF-7 (estrogen responsive proliferative breast cancer model) and MDA-MB-231 (estrogen independent aggressive breast cancer model) cell lines, HeLa (cervical cancer) cell line, and human embryonic kidney (HEK-293) cells. Most of the compounds preferentially inhibited the growth of the aggressive human breast cancer cell lines, MDA-MB-231 in the range of 4.4–30 μM. The two compounds 9 and 29 proved to be better anticancer agents than the standard drug tamoxifen against the MDA-MB-231 cell lines. Mode of action of these compounds was established to be apoptosis, cell cycle arrest and loss of mitochondrial membrane potential.     

Design and synthesis of C3-tethered 1,2,3-triazolo-β-carboline derivatives: Anticancer activity,DNA-binding ability,viscosity and molecular modeling studies

A series of new DNA-interactive C3-tethered 1,2,3-triazolo-β-carboline derivatives have been synthesized via ‘click’ reaction and evaluated for their in vitro cytotoxicity as well as DNA binding affinity. Interestingly, these hybrids have displayed potent in vitro cytotoxicity in comparison to Harmine against the HT-29 (colon cancer) and HGC-27 (gastric cancer) cell lines. The compounds 7f, 7k, 7n and 7s appear to be more effective against the HGC-27 cell line, among which compound 7f showed the highest cytotoxicity (5.44 ± 0.58, IC₅₀ μM). The compounds 7e and 7f appear to be more active against the HT-29 cell line, among which compound 7f exhibited the highest cytotoxicity (3.67 ± 0.62, IC₅₀ μM). To gain more insight into the DNA-binding ability, spectroscopic techniques such as UV–Visible, fluorescence and circular dichroism studies were performed. Viscosity measurements and molecular docking studies substantiate that these compounds indeed bind to DNA via the minor groove.     

New carbazole linked 1,2,3-triazoles as highly potent non-sugar α-glucosidase inhibitors

In the present study, a series of new carbazole linked 1H-1,2,3-triazoles (2–27) were synthesized via click reaction of N-propargyl-9H-carbazole (1) and azides of appropriate acetophenones and heterocycles. Synthesized carbazole triazoles including 7, 9, 10, 19, 20, and 23–26 (IC₅₀ = 0.8 ± 0.01–100.8 ± 3.6 μM), exhibited several folds more potent α-glucosidase inhibitory in vitro activity as compared to standard drug, acarbose. Compounds 2–5, 7–13, and 17–27 did not show any cytotoxicity against 3T3 cell lines, except triazoles 6, and 14–16. Among the series, carbazole triazoles 23 (IC₅₀ = 1.0 ± 0.057 μM) and 25 (IC₅₀ = 0.8 ± 0.01 μM) were found to be most active, and could serve as an attractive building block in the search of new non-sugar derivatives as anti-diabetic agents.     

Synthesis of novel forskolin isoxazole derivatives with potent anti-cancer activity against breast cancer cell lines

Forskolin C₁-isoxazole derivatives (3,5-regioisomers) (11a–e, 14, 15a–h and 15, 16a–g) were synthesized regioselectively by adopting 1,3-dipolar cycloadditions. These derivatives were tested using estrogen receptor positive breast cancer cell lines MCF-7 and BT-474. Majority of the compounds exhibited activity against the p53-positive MCF-7 breast cancer cells but not against the p53-negative BT-474 breast cancer cells. Among forskolin derivatives, compounds 11a, 11c, 14a, 14f, 14g, 14h, 15b, 16g and 17b exhibited higher anti-cancer activity against MCF-7 cell line with an IC₅₀ ≤ 1 µM. The derivative 14f exhibited highest activity in both p53-positive (MCF-7) and p53-negative (BT-474) breast cancer cell lines with an IC₅₀ of 0.5 µM.     

Design and synthesis of pregnenolone/2-cyanoacryloyl conjugates with dual NF-κB inhibitory and anti-proliferative activities

Twenty-five novel pregnenolone/2-cyanoacryloyl conjugates (6–30) were designed and prepared, with the aim of developing novel anticancer drugs with dual NF-κB inhibitory and anti-proliferative activities. Compounds 22 and 27–30 showed inhibition against TNF-α-induced NF-κB activation in luciferase assay, which was confirmed by Western blotting. Among them, compound 30 showed potent NF-κB inhibitory activity (IC₅₀ = 2.5 μM) and anti-proliferative against MCF-7, A549, H157, and HL-60 cell lines (IC₅₀ = 6.5–36.2 μM). The present study indicated that pregnenolone/2-cyanoacryloyl conjugate I can server as a novel scaffold for developing NF-κB inhibitors and anti-proliferative agents in cancer chemotherapy.