Broad-spectrum Antiproliferative Activity Research Articles

Synthesis and in vitro antiproliferative activity of C5-benzyl substituted 2-amino-pyrrolo[2,3-d]pyrimidines as potent Hsp90 inhibitors

A novel series of heat shock protein 90 (Hsp90) inhibitors was identified by X-ray crystal analysis of complex structures at solvent-exposed exit pocket C. The 2-amino-pyrrolo[2,3-d]pyrimidine derivatives, 7-deazapurines substituted with a benzyl moiety at C5, showed potent Hsp90 inhibition and broad-spectrum antiproliferative activity against NCI-60 cancer cell lines. The most potent compound, 6a, inhibited Hsp90 with an IC50 of 36nM and showed a submicromolar mean GI50 value against NCI-60 cell lines. The interaction of 6a at the ATP-binding pocket of Hsp90 was confirmed by X-ray crystallography and Western blot analysis.

Design, synthesis, docking studies and biological evaluation of novel dihydro-1,3,5-triazines as human DHFR inhibitors

A novel series of dihydro-1,3,5-triazine derivatives bearing a heteroatom spiro-ring were designed and synthesized on the basis of molecular flexible docking work, and their biological activities were evaluated. Compounds A2, A5, B1 and B3 showed potent human dihydrofolate reductase (hDHFR) inhibitory activity with IC50 values of 7.46 nM, 3.72 nM, 6.46 nM, 4.08 nM, versus reference drug methotrexate (MTX). From the molecular docking result we concluded that the conformation space generated by deformation of the flexible residue Phe31 is favorable for the binding of the spiro-ring, and inserting heteroatom into spiro ring might increase the binding affinity. There were 24 compounds with broadspectrum antiproliferative activity against several tumor cell lines (HCT116, A549, HL-60, HepG2 and MDA-MB-231) with IC50 values ranging from 0.79 to 0.001 μM. The antitumor activity in vivo of compound A2 was determined in a human alveolar basal epithelial cell line A549 xenograft model. This study offered novel anticancer agents with high inhibitory activity that target hDHFR and have a binding mode of the novel molecular scaffold with hDHFR. This provides potent support for further development of novel hDHFR inhibitors.

Synthesis and biological evaluation of new imidazo[2,1-b]thiazole derivatives as anticancer agents

A series of arylidenehydrazide compounds (3a–3j) were synthesized from [6-(4-chlorophenyl)imidazo[2,1-b]thiazol-3-yl]acetic acid hydrazide. The newly synthesized compounds 3b and 3h were subjected to the National Cancer Institute’s in vitro disease-oriented antitumor screening to be evaluated for antitumor activity. Compound 3b, the most potent compound examined, displayed broad spectrum antiproliferative activity against all of the tested cell lines with log10GI50 values between −4.41 and −6.44. The greatest growth inhibitions were observed against an ovarian cancer cell line(OVCAR-3), a colon cancer cell line (HCT-15), two renal cancer cell lines (CAKI-1 and UO-31) and two leukemia cell lines (CCRF-CEM and SR) with log10GI10 values −6.44, −6.33, −6.11, −6.30, −6.13 and −6.22, respectively.

Discovery of a Nanomolar Multikinase Inhibitor (KST016366): A New Benzothiazole Derivative with Remarkable Broad-Spectrum Antiproliferative Activity.

Herein we report the discovery of compound 6 [KST016366; 4-((2-(3-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)ureido)benzo[d]thiazol-6-yl)oxy)picolinamide] as a new potent multikinase inhibitor through minor structural modification of our previously reported RAF kinase inhibitor A. In vitro anticancer evaluation of 6 showed substantial broad-spectrum antiproliferative activity against 60 human cancer cell lines. In particular, it showed GI50 values of 51.4 and 19 nm against leukemia K-562 and colon carcinoma KM12 cell lines, respectively. Kinase screening of compound 6 revealed its nanomolar-level inhibitory activity of certain oncogenic kinases implicated in both tumorigenesis and angiogenesis. Interestingly, 6 displays IC50 values of 0.82, 3.81, and 53 nm toward Tie2, TrkA, and ABL-1 (wild-type and T315I mutant) kinases, respectively. Moreover, 6 is orally bioavailable with a favorable in vivo pharmacokinetic profile. Compound 6 may serve as a promising candidate for further development of potent anticancer chemotherapeutics.

Phenylethylchromones with In Vitro Antitumor Promoting Activity from Aquilaria filaria

A new chromone, 2-(2-hydroxy-2-phenylethyl)chromone (1), was isolated together with ten known phenylethyl chromones from MeOH extracts of agarwood (Aquilaria filaria). The selected compounds were evaluated in an antiproliferative assay against five human tumor cell lines, including a multidrug-resistant cell line. They were also tested for antitumor promoting activity, as mediated by 12-O-tetradecanoylphorbol-13-acetate-induced activation of the Epstein-Barr virus early antigen in Raji cells. Among all compounds, 4',7-dimethyoxy-6-hydroxychromone (2) displayed broad spectrum antiproliferative activity against all tumor cell lines tested with IC50 values of 25-38 µM, while 8 was selectively inhibitory against multidrug-resistant cells. All tested compounds suppressed tumor promotion at noncytotoxic concentrations. 4',6-Dihydroxyphenylethylchromone (7) exhibited the most potent effect with an IC50 value of 319 mol ratio relative to 12-O-tetradecanoylphorbol-13-acetate. This study is the first to report the antitumor promoting activity of 2-(2-phenylethyl)chromone derivatives, as well as the selective antiproliferative activity of 8 against a multidrug-resistant tumor cell line.

Design, synthesis, and in vitro antiproliferative and kinase inhibitory effects of pyrimidinylpyrazole derivatives terminating with arylsulfonamido or cyclic sulfamide substituents

A novel series of substituted pyrimidine compounds bearing N-phenylpyrazole and terminating with aryl and cyclic sulfonamido moiety were designed, synthesized, and evaluated in vitro as antiproliferative agents against a panel of 53 cell lines of different tissues at the NCI. Among them, compound 1d with p-chlorobenzenesulfonamido terminal moiety, ethylene spacer, and 4-chloro-3-methoxyphenyl ring at position 3 of the pyrazole nucleus showed the highest mean percentage inhibition value over the whole cancer cell line panel at 10 μM concentration. It showed broad-spectrum antiproliferative activity over many cell lines of different cancer types. For instance, compound 1d inhibited the growth of HL-60 (TB), SR leukemia, and T-47D and MCF-7 breast cancer cell line by 135.92%, 119.44%, 95.32%, and 82.03% at 10 μM, respectively. And it inhibited the growth of COLO 205 colon, HT29 colon, BT-549 breast, and ACHN renal cancer cell lines by more than 80% at the same test concentration. However, testing compound 1d upon determining its IC50 against the most sensitive cell lines showed to good extent selectivity against HT29 colon cancer cell line than HL-60 leukemia and MRC-5 lung fibroblasts (normal cells). Compound 1d was further tested against 12 kinases of different kinase families, and the highest inhibitory effect was exerted against RAF1, V600E-B-RAF, and V600K-B-RAF kinases.

Synthesis and Biological Evaluation of Scutellaria Flavone Cyclaneaminol Mannich Base Derivatives as Novel CDK1 Inhibitors.

Cyclin-dependent kinase 1 (CDK1) is the only necessary CDK in the cell proliferation process and a new target in the research and development of anti-cancer drugs. Natural flavones are selective CDK1 inhibitors which can suppress the proliferation of cancer cells. However, their bioavailability is poor. To solve these problems, 6 Scutellaria flavones were isolated from hydrolyzed products of Scutellaria baicalensis and used as lead compounds, 18 Scutellaria flavones cyclane-aminol Mannich base derivatives were semi-synthesized and their biological activity as novel CDK1 inhibitors was evaluated. Results indicated that the biological activity of 8-Hydroxypiperidinemethyl-baicalein (BA-j) is the highest among these compounds. BA-j is a selective CDK1 inhibitor, and has broad-spectrum anti-proliferative activity in human cancer cells (IC50 12.3μM). BA-j can capture oxygen free radicals (.O2(-)) and selectively increase intracellular H2O2 level in cancer cells and activated lymphocytes, thus inducing their apoptosis rather than in normal cells. These findings suggest that BA-j selectively induces apoptosis in cancer and activated lymphocyte by controlling intracellular H2O2 level, and can be developed into a novel anti-proliferative agent for the treatment of cancer, AIDS, and some immune diseases.

Novel 5-substituted-2-anilinoquinolines with 3-(morpholino or 4-methylpiperazin-1-yl)propoxy moiety as broad spectrum antiproliferative agents: Synthesis, cell based assays and kinase screening

A series of new 2-anilinoquinolines possessing 3-(morpholino or 4-methylpiperazin-1-yl)propoxy moiety at C5 of quinoline has been designed and synthesized as potential anticancer agents. Their antiproliferative activities were evaluated against a panel of 60 cancer cell lines at NCI and compared with gefitinib as a reference compound. Most of the tested compounds displayed potent and broad spectrum antiproliferative activities. Compounds 7d, 7f and 7g showed strong inhibitory and lethal effects at 10μM concentration. Moreover, they manifested superior potencies and efficacies than gefitinib across the most tested cell lines. Compound 7d, with 4-chloro-3-trifluoromethylphenyl group, proved to be the most potent and efficacious derivative in this series, with mean GI50 and TGI values of 1.62μM and 3.47μM, respectively. Kinase screening of 7d against a panel of 47 oncogenic kinases revealed its selective inhibitory effect (96% inhibition) towards TrkA kinase. Furthermore, the most potent compounds showed low cytotoxic effects against HFF-1 normal cell line.

Design, synthesis, broad-spectrum antiproliferative activity, and kinase inhibitory effect of triarylpyrazole derivatives possessing arylamides or arylureas moieties

A novel series of 1,3,4-triarylpyrazole derivatives possessing terminal arylamide or arylurea terminal moieties has been designed and synthesized. Their in vitro antiproliferative activities were investigated against a panel of 58 cell lines of nine different cancer types at the NCI, USA. The urea analogues 2b, 2c, and 2f as well as the amide derivatives 3e and 3f exerted the highest mean % inhibition values over the 58 cell line panel at 10 μM, and thus were further tested in 5-dose testing mode to determine their GI50, TGI, and LC50 values. The above mentioned compounds have shown stronger antiproliferative activities in terms of potency and efficacy upon comparing their results with Sorafenib as a reference compound. Among them, compounds 2c and 2f possessing 3,4-dichlorophenylurea terminal moiety showed the highest mean %inhibition value of about 99.85 and 104.15% respectively over the 58-cell line panel at 10 μM concentration. Also compounds 2b, 3e, and 3f exhibited mean % inhibition over 80% at 10 μM concentration. The GI50 value of compound 3e over K-562 cancer cell line was 0.75 μM. Accordingly, compound 2f was screened over seven kinases at a single-dose concentration of 10 μM to profile its kinase inhibitory activity. Interestingly, the compound showed highly inhibitory activities (90.44% and 87.71%) against BRAF (V600E) and RAF1 kinases, respectively. Its IC50 value against BRAF (V600E) was 0.77 μM. Compounds 2b, 2c, 2f, 3e, and 3f exerted high selectivity towards cancer cell lines than L132 normal lung cells.

Broad-spectrum antiproliferative activity of a series of 6-(4-fluorophenyl)-5-(2-substituted pyrimidin-4-yl)imidazo[2,1-b]thiazole derivatives

This article described the synthesis and in vitro antiproliferative activities a series of 6-(4-fluorophenyl)-5-(2-substituted pyrimidin-4-yl)imidazo[2,1-b]thiazole derivatives. The nine target compounds were tested for in vitro antitumor effect against a panel of 55 cell lines of nine different cancer types at the NCI, and their activities were compared with that of Sorafenib as a reference standard drug. Compounds 1d and 1e possessing terminal arylamide moiety exerted superior potencies than Sorafenib against different cancer cell lines. Both compounds were more potent than Sorafenib against UO-31 renal cancer cell line and MCF7 breast cancer cell line. Compound 1d was also more potent than Sorafenib against COLO 205 colon cancer cell line, and compound 1e showed higher potency than Sorafenib against OVCAR-3 ovarian cancer cell line and DU-145 prostate cancel cell line also. For instance, the IC50 value of compound 1e against DU-145 prostate cancer cell line was 1.04 μM, which is threefold more potent than Sorafenib.

Synthesis, antiproliferative activity, and molecular docking studies of curcumin analogues bearing pyrazole ring

Several curcumin analogues bearing pyrazole were synthesized and characterized by IR, NMR, and mass spectral data. There were four tested compounds among 11 synthesized compounds, which were evaluated for antiproliferative activity and showed significant activity in both one-dose and five-dose assays. The antiproliferative effects were tested on a panel of 60 cell lines, according to the National Cancer Institute screening protocol. The most active compounds among the series were 3,5-bis(4-hydroxy-3-methylstyryl)-1H-pyrazole-1-carboxamide (3k) which showed mean percent growth inhibition of 116.09 in one-dose assay at 10 µM, and GI50 values were ranging between 0.0912 and 2.36 µM in five-dose assay. The best results were recorded on the leukaemia cell lines with value ranging from 0.0912 to 0.365 µM. All the tested compounds showed broad-spectrum antiproliferative activity over different cancer cell lines. When compared with the standard drug paclitaxel, the compound 3k showed superior activity on nearly 42 cell lines. The molecular docking study was performed to explore the binding interaction of these curcumin analogues with the active site of EGFR tyrosine kinase (EGFR-TK). The hydroxyl group of both phenyl rings was important for the rein-geminated hydrogen bonding by either side chain or backbone with the active site of EGFR-TK. Four curcumin analogues were evaluated for their antiproliferative activity and showed promising results. The molecular docking studies showed that all the compounds (3a–k) were well accommodated in the EGFR tyrosine kinase.

Discovery of a broad spectrum antiproliferative agent with selectivity for DDR1 kinase: cell line-based assay, kinase panel, molecular docking, and toxicity studies

Herein, we report compound KST9046, a new agent possessing quinazoline-urea scaffold. Preliminary biological evaluation done by the National Cancer Institute (NCI), USA, showed a great inhibitory effect of KST9046 over the 60 cell-line tumor panel. Accordingly, it was selected for a dose-response assay; a broad spectrum antiproliferative activity with GI50 ranging from 1.3 to 3.9 µM was exerted. To explore a potential kinase inhibitory effect, KST9046 was applied at a single dose of 10 µM against a kinase panel of 347 different enzymes representing >50% of the predicted human protein kinome. Interestingly, selective inhibition of 76% was observed on DDR1 kinase. Further, KST9046 showed an IC50 value of 4.38 µM for DDR1. A molecular docking model presented KST9046 as a potential type III inhibitor for DDR1 kinase with an allosteric mode of interaction, which may offer an explanation for its selectivity. As further investigation, CYP450 assay was carried out for KST9046, it showed a promising toxicity profile against four different isoforms. Based on these findings, KST9046 can be further evaluated as a promising safe new hit for the development of broad spectrum anticancer agents with a selectivity for DDR1 kinase.

Synthesis and antileukemic activities of C1–C10-modified parthenolide analogues

Parthenolide (PTL) is a sesquiterpene lactone natural product with anti-proliferative activity to cancer cells. Selective eradication of leukemic stem cells (LSCs) over healthy hematopoietic stem cells (HSCs) by PTL has been demonstrated in previous studies, which suggests PTL and related molecules may be useful for targeting LSCs. Eradication of LSCs is required for curative therapy. Chemical optimizations of PTL to improve potency and pharmacokinetic parameters have focused largely on the α-methylene-γ-butyrolactone, which is essential for activity. Conversely, we evaluated modifications to the C1–C10 olefin and benchmarked new inhibitors to PTL with respect to inhibitory potency across a panel of cancer cell lines, ability to target drug-resistant acute myeloid leukemia (AML) cells, efficacy for inhibiting clonal growth of AML cells, toxicity to healthy bone marrow cells, and efficiency for promoting intracellular reactive oxygen species (ROS) levels. Cyclopropane 4 was found to possess less toxicity to healthy bone marrow cells, enhanced potency for the induction of cellular ROS, and similar broad-spectrum anti-proliferative activity to cancer cells in comparison to PTL.

Synthesis and broad-spectrum antiproliferative activity of diarylamides and diarylureas possessing 1,3,4-oxadiazole derivatives.

A series of diarylamides and diarylureas possessing 1,3,4-oxadiazole scaffold was designed and synthesized. Their in vitro antiproliferative activities were tested against a panel of 58 cell lines of nine different cancer types at the NCI, and compared with Sorafenib as a reference compound. Most of the compounds showed strong and broad-spectrum antiproliferative activities. The diarylurea compound 2g possessing 4-chloro-3-(trifluoromethyl)phenyl terminal moiety showed the highest mean % inhibition value of about 100% over the 58-cell line panel at 10μM concentration. Also compounds 2h, 2l, 2m exhibited mean % inhibition over 90% at 10μM concentration. The IC50 value of compound 2b over SNB-75 CNS cancer cell line was 0.65μM. Compound 2h also exerted submicromolar IC50 values of 0.67, 0.80, and 0.87μM against PC-3 prostate cancer cell line, HCT-116 colon cancer cell line, and ACHN renal cancer cell line, respectively. Compound 2h showed comparable efficacy to Sorafenib.

Design, synthesis, and in-vitro antiproliferative effect of some novel 1,3,4-oxadiazole derivatives bearing benzimidazole nucleus

Background and objectives Development of a novel compound containing a heterocyclic nucleus as an anticancer therapeutic agent is the most important focal point in medicinal chemistry. Programmed cell death or apoptosis is a fundamental phenomenon and plays a central role in immune regulation, embryogenesis, and general tissue homeostasis. Therefore, identification of novel potent, selective, and less toxic anticancer agents is one of the most crucial concerns. Materials and methods A series of 4-{1-[(4-acetyl-5-(substituted)-4,5-dihydro-1,3,4-oxadiazol-2-yl)methyl]-5-nitro-1 H- benzimidazol-2-yl}benzonitrile 6 (I-IV) and novel 4-{5-substituted-1-[(4,5-disubstituted)-4,5-dihydro-1,3,4-oxadiazol-2-yl)methyl]-5-nitro-1 H- benzimidazol-2-yl}benzonitrile 7 (V-XXXIII) derivatives were synthesized. Results and conclusion Nine of them were selected by the Department of Biotechnology Drug Discovery R&D, Century Pharmaceuticals Ltd, for evaluation of their in-vitro anticancer activity. Three of the investigated compounds, 7.X, 7.XIX , and 7.XXIV , displayed in-vitro anticancer activity in the primary assay. These compounds were selected for a full anticancer screening against a three-cell panel MTT assay, and they showed a nonselective broad spectrum antiproliferative activity against L929, HCT15, and Hep2 cancer cell lines. Compound 7.XIX showed antiproliferative activity, which can be comparable to that of 5-fluorouracil, methotrexate, and daunorubicin, and this compound has been identified as a promising lead compound.

Synthesis and in vitro antiproliferative activity of new 1,3,4-oxadiazole derivatives possessing sulfonamide moiety.

Synthesis of a new series of 1,3,4-oxadiazole derivatives possessing sulfonamide moiety is described. Their in vitro antiproliferative activities against NCI-58 human cancer cell lines of nine different cancer types were tested. Compound 1k with p-methoxybenzenesulfonamido moiety showed the highest mean %inhibition value over the 58 cell line panel at 10 μM concentration. It showed broad-spectrum antiproliferative activity over many cell lines of different cancer types. For instance, compound 1k inhibited the growth of T-47D breast cancer cell line by 90.47% at 10 μM. And it inhibited growth of SR leukemia, SK-MEL-5 melanoma, and MDA-MB-468 breast cancer cell lines by more than 80% at the same test concentration. Compound 1k showed superior activity than Paclitaxel and Gefitinib against the most sensitive cell lines.

Novel metal complexes of naphthalimide–cyclam conjugates as potential multi-target receptor tyrosine kinase (RTK) inhibitors: Synthesis and biological evaluation

A novel series of metal complexes of naphthalimide–cyclam conjugates were synthesized and their in vitro antitumor activities were evaluated. The newly-synthesized compounds showed huge diversity of antiproliferative potency due to variety of metal ions and length of alkyl chains, among which the Zn(II) and Cr(III) complexes exhibited comparable antiproliferative activities with amonafide via multiple tyrosine kinase inhibition. Further research revealed that the representative compound 8a displayed broad-spectrum antiproliferative activity against 15 cancer cell lines with average IC50 value 10.18 ± 3.25 μM, and effective antiangiogenic activity on human microvascular endothelial cells (HMEC-1). In brief, metal complexes of naphthalimide–cyclam conjugates were firstly designed and synthesized as multi-target tyrosine kinase inhibitors and proved of their antitumor capacities.

Synthesis and Structure Activity Relationship Study of N-substituted 3,5-diarylidenepiperidin- 4-ones as Potential Antitumor Agents

A new series of N-substituted diarylidenepiperidin-4-ones was synthesized and screened for their possible anticancer activity at the NCI Developmental Therapeutic Program. Almost all the synthesized compounds showed more potent antiproliferative activity than curcumin. The most active compound in this study was 3,5-bis(4-bromobenzylidene)-1-propanoylpiperidin-4-one (8a) with MG-MID GI50, TGI, and LC50 values of 0.35, 1.62 and 9.12 µM, respectively. Compound 8a displayed broad spectrum antiproliferative activity with GI50 values below 1 µM in 81% of the tested cell lines and was found to be two folds more potent than EF-24. A detailed study of the structure activity relationship of the N-substitution was also described.

Diarylureas and Diarylamides with Pyrrolo[2,3-<i>d</i>]pyrimidine Scaffold as Broad-Spectrum Anticancer Agents

A series of diarylureas and diarylamides possessing pyrrolo[2,3-d]pyrimidine scaffold was designed and synthesized. The in vitro antiproliferative activities of a selected group of the target compounds against NCI-60 cell line panel were tested and compared with Sorafenib and Imatinib as reference compounds. Most of the compounds showed strong and broad-spectrum antiproliferative activities. Compounds IVa, IVb, and IVd with benzamido moiety at position 4 of the pyrrolo[2,3-d]pyrimidine nucleus, para-disubstituted phenyl ring at N1-position of pyrrolo[2,3-d]pyrimidine scaffold, and urea linker showed strong and broad-spectrum anticancer results with high potencies and efficacies. In addition, the amide derivatives Vb and Vc demonstrated one-digit nanomolar IC50 values over two and one cell line(s), respectively. Amid all the target compounds, compound IVa demonstrated the best results in both one-dose and five-dose testing modes. It showed 109.18% mean % inhibition over the NCI-60 cancer cell line panel at 10 µM concentration, submicromolar 50% inhibitory concentration (IC50) values over eight cell lines of eight different cancer types, and high efficacy with total growth inhibition (TGI) and 50% lethal concentration (LC50) values less than 4.22 µM over three colon, ovarian, and prostate cancer cell lines. It showed superior potency and efficacy to Sorafenib and Imatinib over most of the tested cell lines.

New triarylpyrazoles as broad-spectrum anticancer agents: Design, synthesis, and biological evaluation

A new series of diarylureas and diarylamides possessing 1,3,4-triarylpyrazole scaffold was designed and synthesized. Their in vitro antiproliferative activities against NCI-60 cell line panel were tested. Most of the compounds showed strong and broad-spectrum antiproliferative activities. Compound 18 exerted sub-micromolar IC50 values over all the subpanels of nine different cancer types. Its IC50 value over MDA-MB-435 melanoma cell line was 27 nM. Compounds 10–13, 22, and 23 possessing urea spacer exerted lethal effect over the NCI-60 panel with mean %inhibitions more than 100% in single-dose testing. Compounds 13 and 23 with urea linker and 3′,5′-bis(trifluoromethyl)phenyl terminal ring showed the highest mean %inhibition over the NCI-60 panel in single-dose testing, and showed high potencies and broad-spectrum anticancer activities in five-dose testing.