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.     

Design and discovery of thioether and nicotinamide containing sorafenib analogues as multikinase inhibitors targeting B-Raf,B-RafV600E and VEGFR-2

New sorafenib derivatives containing thioether and nicotinamide moiety were designed and synthesized as B-Raf, B-Raf^V600E and VEGFR-2 multikinase inhibitors. Their in vitro enzymatic inhibitory activities against B-Raf, B-Raf^V600E and VEGFR-2 and their antiproliferative activities against HCT-116 and B16BL6 cell lines were evaluated and described. Most of the compounds showed potent activities against both cell lines and specific kinases. Compounds a1, b1 and c4, which exhibited the most potent inhibitory activities against B-Raf with IC₅₀ of 21?nM, 27?nM and 17?nM, B-Raf^V600E with IC₅₀ of 29?nM, 28?nM and 16?nM, VEGFR-2 with IC₅₀ of 84?nM, 46?nM and 63?nM, respectively, and good antiproliferative activities, also demonstrated competitive antiangiogenic activities to sorafenib in in vitro HUVEC tube formation assay.     

Discovery of 4-aminoquinazoline—urea derivatives as Aurora kinase inhibitors with antiproliferative activity

Two series of 20 novel 4-aminoquinazoline—urea derivatives have been designed and synthesized. The entire target compounds were investigated for their in vitro antiproliferative activity against six human cancer cell lines (K562, U937, A549, NCI-H661, HT29 and LoVo) using the MTT-based assay. Most compounds showed significant antiproliferative activities against four solid tumor cell lines, but no or poor activities against two leukemia cell lines. Furthermore, the target compounds were screened for Aurora A/B kinases inhibitory activity. Among them, 7c, 7d, 8c, and 8d are more potent against Aurora A kinase than ZM447439. Docking study of compounds 7d and ZM447439 revealed that they bound strongly to the ATP-binding sites of Aurora A and B. Thus, they may be promising lead compounds for the development of novel anti-tumor drug potentially via inhibiting Aurora kinases.     

Discovery of 4,6-Disubstituted Pyrimidine Derivatives as Novel Dual VEGFR2/FGFR1 Inhibitors

Abnormalities in the FGFRs signaling pathway and VEGFR2 amplification often occur in a variety of tumors, and they synergistically promote tumor angiogenesis. Studies have shown that the up-regulation of FGF-2 is closely related to the resistance of VEGFR2 inhibitors. Activation of the FGFRs signal is a signal of compensatory angiogenesis after VEGFR2 resistance. Dual VEGFR2/FGFR1 inhibitors contribute to overcoming the resistance of VEGFR2 inhibitors and inhibit tumor growth significantly. Based on this, we designed and synthesized a series of 4,6-disubstituted pyrimidine derivatives as dual VEGFR2/FGFR1 inhibitors by the molecular hybridization strategy. 3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-{6-[(4-methoxyphenyl)amino]pyrimidin-4-yl}-1-methylurea ( 8b ) had the best inhibitory activities against VEGFR2 and FGFR1 at 10 μM (82.2 % and 101.0 %, respectively), it showed moderate antiproliferative activities against A549 and KG-1 cell lines as well. Besides, molecular docking was also carried out to study the binding mode of 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-{6-[(4-methoxyphenyl)-amino]-pyrimidin-4-yl}-1-methylurea ( 8b ) with VEGFR2 and FGFR1. These studies reveal that this series of compounds deserve further optimization.     

Design, synthesis and antitumor activities of novel bis-aryl ureas derivatives as Raf kinase inhibitors

A series of novel bis-aryl ureas containing trifluoromethyl imidazolyl group targeting Raf kinase were designed and synthesized based on the lead compound of Sorafenib. All the prepared compounds were evaluated for their in vitro antiproliferative activities against three human cancer cell lines including MDA-MB-231 (breast), BGC-823 (gastric), and SMMC-7721 (liver). Several compounds from the series exhibited excellent antitumor activities against all three tested cancer lines. Further their inhibitory activities against Raf kinase were investigated, and three compounds (11c, 11d, and 11p) demonstrated better activities than contrast drug Sorafenib. Especially compound 11c was found to be a potent and selective Raf kinase inhibitor and could be considered as a candidate compound for further development.     

Design, synthesis, and in vitro antiproliferative activity of novel Dasatinib derivatives

Two series of novel Dasatinib derivatives have been designed and synthesized, with their in vitro cytostatic effect screened on human chronic myeloid leukemia cell line K562 and human myeloid leukemia cell line U937. Some target compounds demonstrated significant inhibitory activities against both cell lines. Compared to the contrast drug Dasatinib, 1b, 1c, 1d, 1e and 1f were found to demonstrate more potent antitumor activities. The structures of all the newly synthesized compounds were determined by (1)H NMR and (13)C NMR.     

Synthesis and biological evaluation of N-aryl salicylamides with a hydroxamic acid moiety at 5-position as novel HDAC-EGFR dual inhibitors

A novel series of N-aryl salicylamides with a hydroxamic acid moiety at 5-position were synthesized efficiently. Their activities against EGFR kinase and HDACs were evaluated. All compounds displayed inhibitory activity against EGFR and HDACs. The antiproliferative activities of synthesized compounds were evaluated by MTT method against human cancer cell lines A431, A549 and HL-60. Compound 1o showed the most potent inhibitory activity against A431 and A549. Compounds 1k and 1n exhibited higher potency against HL-60 than gefitinib and SAHA. N-Aryl salicylamides with a hydroxamic acid moiety at 5-position is another new HDAC-EGFR dual inhibitors.     

Design,synthesis, and biological evaluation of novel aminopyrimidinylisoindolines as AXL kinase inhibitors

A novel series of aminopyrimidinylisoindoline derivatives 1a-w having an aminopyrimidine scaffold as a hinge region binding motif were designed and synthesized. Among them, six compounds showed potent inhibitory activities against AXL kinase with IC₅₀ values of submicromolar range. Especially, compound 1u possessing (4-acetylpiperazin-1-yl)phenyl moiety exhibited extremely excellent efficacy (IC₅₀?=?<0.00050?μM). Their in vitro antiproliferative activities were tested over five cancer cell lines. Most compounds showed good antiproliferative activities against HeLa cell line. The kinase panel profiling of 50 different kinases and the selected inhibitory activities for the representative compound 1u were carried out. The compound 1u exhibited excellent inhibitory activities (IC₅₀?=?<0.00050, 0.025, and 0.050?μM for AXL, MER, and TYRO3, respectively) against TAM family, together with potent antiproliferative activity against MV4-11 cell line (GI₅₀?=?0.10?μM) related to acute myeloid leukemia (AML).     

Synthesis,antiproliferative and antimicrobial activity of new Mannich bases bearing 1,2,4-triazole moiety

Abstract

This study presents the synthesis, antiproliferative and antimicrobial evaluation of a new series of Mannich base derivatives containing 1,2,4-triazole system. New compounds were prepared by the reaction of 4,5-disubstituted 1,2,4-triazole-3-thiones with formaldehyde and various amines. The structures of the prepared compounds were confirmed by means of ¹H NMR, ¹³C NMR and elemental analyses. Twelve compounds were evaluated for their in vitro antiproliferative activities against six chosen cancer cell lines. All synthesized compounds were screened for their in vitro antimicrobial activity by using the agar dilution technique. For 17 potentially active compounds, their antibacterial activity was confirmed on the basis of MIC (minimal inhibitory concentration) by broth microdilution method using the reference Gram-positive and Gram-negative bacterial strains.     

Synthesis,computational studies and antiproliferative activities of coumarin-tagged 1,3,4-oxadiazole conjugates against MDA-MB-231 and MCF-7 human breast cancer cells

A novel library of coumarin tagged 1,3,4 oxadiazole conjugates was synthesized and evaluated for their antiproliferative activities against MDA-MB-231 and MCF-7 breast cancer cell lines. The evaluation studies revealed that compound 9d was the most potent molecule with an IC₅₀ value of <5?µM against the MCF-7 cell line. Interestingly, compounds 10b and 11a showed a similar trend with lower inhibitory concentration (IC₅₀?=?7.07?µM), in Estrogen Negative (ER?) cells than Estrogen Positive (ER+) cells. Structure–activity relationship (SAR) studies revealed that conjugates bearing benzyl moieties (9b, 9c and 9d) had superior activities compared to their alkyl analogues. The most potent compound 9d showed ～1.4?times more potent activity than tamoxifen against MCF-7 cell line; while the introduction of sulfone unit in compounds 11a, 11b and 11c resulted in significant cytotoxicity against both MCF-7 and MDA-MB-231 cell lines. These results were further supported by docking studies, which revealed that the stronger binding affinity of the synthesized conjugates is due to the presence of sulfone unit attached to the substituted benzyl moiety in their pharmacophores.     

Design, synthesis and CoMFA studies of N1-amino acid substituted 2,4,5-triphenyl imidazoline derivatives as p53-MDM2 binding inhibitors

A series of novel N1-amino-acid substituted 2,4,5-triphenyl imidazoline derivatives was designed and synthesized based on our previous studies. All synthesized target compounds were screened for their p53-MDM2 binding inhibitory activities and anti-proliferative activities against five cancer cell lines. Among them, twelve compounds displayed improved binding inhibitory activities and most compounds showed higher cell growth inhibition activities with IC(50) values in the low micromolar range. Compound 6c exhibited marked p53-MDM2 binding inhibitory activity (IC(50)=0.59 μM) which was eightfold more potent than that of Nutlin-1 (IC(50)=4.78 μM). CoMFA analysis was performed based on obtained biological data and resulted in a statistically significant CoMFA model with high predict abilities (q(2)=0.645, r(2)=0.979).     

Synthesis and antiproliferative activity of thiazolidine analogs for melanoma

We have previously described 2-aryl-thiazolidine-4-carboxylic acid amides as a novel class of antiproliferative agents for prostate cancer. Screening these compounds with melanoma cell lines revealed that several of them have potent antiproliferative activity and selectivity against melanoma. To further improve the potency and selectivity, we synthesized a new series of analogs and tested them in two melanoma cell lines and fibroblast cells (negative controls). Comparison of anticancer effects of these compounds with a standard chemotherapeutic agent, sorafenib, showed that they are very effective in killing melanoma cells with low micromolar to nanomolar antiproliferative activity and provide us a new lead for developing potential drugs for melanoma.     

Discovery of new VEGFR-2 inhibitors based on bis([1, 2, 4]triazolo)[4,3-a:3',4'-c]quinoxaline derivatives as anticancer agents and apoptosis inducers

Herein, a new wave of bis([1, 2, 4]triazolo)[4,3-a:3'',4''-c]quinoxaline derivatives have been successfully designed and synthesised. The synthesised derivatives were biologically investigated for their cytotoxic activities against HepG2 and MCF-7. Also, the tested compounds were further examined in vitro for their VEGFR-2 inhibitory activity. The most promising derivative 23j was further investigated for its apoptotic behaviour in HepG2 cell lines using flow cytometric and western-plot analyses. Additional in-silico studies were performed to predict how the synthesised compounds can bind to VEGFR-2 and to determine the drug-likeness profiling of these derivatives. The results revealed that compounds 23a, 23i, 23j, 23l, and 23n displayed the highest antiproliferative activities against the two cell lines with IC₅₀ values ranging from 6.4 to 19.4 µM. Furthermore, compounds 23a, 23d, 23h, 23i, 23j, 23l, 23 m, and 23n showed the highest VEGFR-2 inhibitory activities with IC₅₀ values ranging from 3.7 to 11.8 nM, comparing to sorafenib (IC₅₀ = 3.12 nM). Moreover, compound 23j arrested the HepG2 cell growth at the G2/M phase and induced apoptosis by 40.12% compared to the control cells (7.07%). As well, such compound showed a significant increase in the level of caspase-3 (1.36-fold), caspase-9 (2.80-fold), and BAX (1.65-fold), and exhibited a significant decrease in Bcl-2 level (2.63-fold).     

Design, synthesis, and antiproliferative activity of new 1H-pyrrolo[3,2-c]pyridine derivatives against melanoma cell lines. Part 2

A new series of diarylureas and diarylamides possessing 1H-pyrrolo[3,2-c]pyridine scaffold was designed and synthesized. Their in vitro antiproliferative activities against A375P human melanoma cell line and NCI-9 human melanoma cell line panel were tested. All the target compounds, except three amino derivatives 8g, h and 9h, demonstrated superior potencies against A375P to Sorafenib. In addition, compounds 8a and 9b-f demonstrated higher potencies than Vemurafenib against A375P. Compounds 8c and 9b were 7.50 and 454.90 times, respectively, more selective towards A375P melanoma cells over NIH3T3 fibroblasts. Furthermore, compounds 8d, e and 9a-d, f demonstrated very high potencies against the nine tested melanoma cell lines at the NCI. The bisamide derivatives 9a-c, f showed 2-digit nanomolar IC(50) values over different cell lines of the NCI-9 melanoma cell lines.     

Discovery of novel 4-aryl-thieno[1,4]diazepin-2-one derivatives targeting multiple protein kinases as anticancer agents

A series of 4-aryl-thieno[1,4]diazepin-2-one were synthesized and evaluated for their antiproliferative activities against the A375P melanoma and U937 hematopoietic cell lines. Several compounds showed very potent antiproliferative activities toward both cell lines and the activities were better than that of sorafenib, the reference standard. Derivatives were made as amide (8a–8i, 9a–9m) and urea (10a–10d, 11a–11d) with diverse hydrophobic moieties. One of the most potent inhibitor 10d, 1-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(4-(2-oxo-2,3-dihydro-1H-thieno [3,4-b][1,4]diazepin-4-yl)phenyl)urea was found to be very potent inhibitor of multi-protein kinases including FMS kinase (IC₅₀?=?3.73?nM) and is a promising candidate for further development in therapeutics for cancer.     

Synthesis and antitumor activities of novel hybrid molecules containing 1,3,4-oxadiazole and 1,3,4-thiadiazole bearing Schiff base moiety

A series of novel hybrid molecules containing 1,3,4-oxadiazole and 1,3,4-thiadiazole bearing Schiff base moiety were designed, synthesized and evaluated for their in vitro antitumor activities against SMMC-7721, MCF-7 and A549 human tumor cell lines by CCK-8 assay. The bioassay results demonstrated that most of the tested compounds showed potent antitumor activities, and some compounds exhibited stronger effects than positive control 5-fluorouracil (5-FU) against various cell lines. Among these compounds, compound 8d showed the best inhibitory effect against SMMC-7721 cells, with IC₅₀ value of 2.84 μM. Compounds 8k and 8n displayed highly effective antitumor activities against MCF-7 cells, with IC₅₀ values of 4.56 and 4.25 μM, respectively. Compounds 8a and 8n exhibited significant antiproliferative activity against A549 cells, with IC₅₀ values of 4.11 and 4.13 μM, respectively. The pharmacological results suggest that the substituents of phenyl ring on the 1,3,4-oxadiazole are vital for modulating antiproliferative activities against various tumor cell lines.     

Synthesis,Antiproliferative Evaluation,and Molecular Docking Study of Novel Longifolene-Derived Tetraline Fused Thiazole-Amide Derivatives

Twenty novel longifolene-derived tetraline fused thiazole-amide compounds were synthesized from longifolene, a renewable natural resource. Their structures were characterized by FT-IR, NMR, ESI-MS, and elemental analysis. The in vitro antiproliferative activity of these compounds against SK-OV-3 ovarian cancer cell lines, MCF-7 human breast cancer cell lines, HepG2 human liver cancer cell lines, A549 human lung adenocarcinoma cell lines, and T-24 human bladder cancer cell lines was tested by MTT assay. Compounds 6a – 6c displayed significant and broad-spectrum antiproliferative activity against almost the tested cancer cell lines with IC₅₀ in the range of 7.84 to 55.88 μM, of which compound 6c exhibited excellent antiproliferative activities with 7.84 μM IC₅₀ against SKOV-3, 13.68 μM IC₅₀ against HepG2, 15.69 μM IC₅₀ against A549, 19.13 μM IC₅₀ against MCF-7, and 22.05 μM IC₅₀ against T-24, showing better and broad-spectrum antiproliferative effect than that of the positive control 5-FU. Furthermore, the action model was analyzed by the molecular docking study. Some intriguing structure-activity relationships were found and discussed herein by DFT theoretical calculation.     

Design, synthesis and biological evaluation of novel chalcone derivatives as antitubulin agents

A series of novel chalcone derivatives have been designed and synthesized, and their biological activities were also evaluated as potential inhibitors of tubulin. These compounds were assayed for growth-inhibitory activity against MCF-7 and A549 cell lines in vitro. Compound 3d showed the most potent antiproliferative activity against MCF-7 and A549 cell lines with IC(50) values of 0.03 and 0.95 μg/mL and exhibited the most potent tubulin inhibitory activity with IC(50) of 1.42 μg/mL. Docking simulation was performed to insert compound 3d into the crystal structure of tubulin at colchicines binding site to determine the probable binding model. Based on the preliminary results, compound 3d with potent inhibitory activity in tumor growth may be a potential anticancer agent.     

Design and synthesis of novel imidazo[4,5-b]pyridine based compounds as potent anticancer agents with CDK9 inhibitory activity

New imidazo[4,5-b]pyridine derivatives were designed, synthesized and screened for their anticancer activity against breast (MCF-7) and colon (HCT116) cancer cell lines. Nine compounds (I, II, IIIa, IIIb, IV, VI, VIIa, VIII, IX) showed significant activity against MCF-7, while six compounds (I, VIIc, VIIe, VIIf, VIII, IX) elicited a remarkable activity against HCT116. Compounds showing significant anticancer activity revealed remarkable CDK9 inhibitory potential (IC₅₀ = 0.63–1.32 μM) relative to sorafenib (IC₅₀ = 0.76 μM). Moreover, a molecular docking study was performed to illustrate the binding mode of the most active compounds in the active site of CDK9 where it revealed superior binding affinity relative to the natural ligand (T3C).     

Methotrexate gamma-hydroxamate derivatives as potential dual target antitumor drugs

A series of new aminopteroyl-based hydroxamate derivatives were synthesized and tested in vitro in cell culture models as potential dual target drugs. These compounds were designed to target two families of enzymes, matrix metalloproteinases (MMP) and a folate enzyme, dihydrofolate reductase (DHFR). These enzymes are the components of two unrelated cellular pathways and they are often over-expressed in metastasizing tumors. In addition to the synthesis and full structural characterization of the hybrid molecules, we describe their inhibitory activities against a series of MMPs (MMP-2, MMP-7, MMP-9, MMP-14) and DHFR, as well as their antiproliferative activity in three cancer cell lines. The new hydroxamate derivatives of MTX proved to be effective inhibitors of MMPs and DHFR in the micromolar and nanomolar range, respectively. Furthermore, they showed strong antiproliferative activity against A549 cells (non-small cell lung carcinoma), and PPC-1 and Tsu-Pr1 prostate cancer cell lines. Therefore, based on the present results, these bi-functional drugs may be good candidates to target specific tumors in animal models due to potential combined effects on two pathways crucial for tumor development.