Synthesis of 2-,4,-6-, and/or 7-substituted quinoline derivatives as human dihydroorotate dehydrogenase (hDHODH) inhibitors and anticancer agents: 3D QSAR-assisted design

Following our research for human dihydroorotate dehydrogenase (hDHODH) inhibitors as anticancer agents, herein we describe 3D QSAR-based design, synthesis and in vitro screening of 2-,4,-6-, and/or 7-substituted quinoline derivatives as hDHODH inhibitors and anticancer agents. We have designed 2-,4,-6-, and/or 7-substituted quinoline derivatives and predicted their hDHODH inhibitory activity based on 3D QSAR study on 45 substituted quinoline derivatives as hDHODH inhibitors, and also predicted toxicity. Designed compounds were docked into the binding site of hDHODH. Designed compounds which showed good predictive activity, no toxicity, and good docking score were selected for the synthesis, and in vitro screening as hDHODH inhibitors in an enzyme inhibition assay, and anticancer agents in MTT assay against cancer cell lines (HT-29 and MDA-MB-231). Synthesized compounds 7 and 14 demonstrated IC₅₀ value of 1.56?µM and 1.22?µM, against hDHODH, respectively, and these are our lead compounds for the development of new hDHODH inhibitors and anticancer agents.     

Novel γ-lactone derivatives from Trigonostemon heterophyllus with their potential antiproliferative activities

Two novel γ-lactone derivatives, trigoheterophines A (1) and B (2), together with four known furan derivatives (3–6), were isolated from the stems and leaves of Trigonostemon heterophyllus. The structures of 1 and 2 were elucidated by extensive spectroscopic methods and the known compounds were identified by comparing with the data reported in literature. Among them, trigoheterophines A (1) and B (2) represent an unusual type of γ-lactone derivatives, possessing 21 carbon atoms on the carbon skeleton, and known compouds (3–6) are rare furan derivatives in the plant kingdom with diverse long-chain hydrocarbyl groups as substituents at C-4. All isolated compounds were evaluated for their antiproliferative activities against five human cancer cell lines: HL-60, SMMC-7721, A-549, MCF-7 and SW480 in vitro. Compounds 1–6 showed significant antiproliferative effects against various human cancer cell lines with IC₅₀ values ranging from 0.28 to 12.06 μM. These findings suggest that the discoveries of these novel γ-lactone derivatives and furan derivatives with significant antiproliferative activities isolated from T. heterophyllus could be of great importance to the development of new anticancer agents.     

Design,synthesis, molecular modeling and biological evaluation of novel 1H-pyrazolo[3,4-b]pyridine derivatives as potential anticancer agents

In trying to develop new anticancer agents, a series of 1H-pyrazolo[3,4-b]pyridine derivatives was designed and synthesized. Fifteen compounds were evaluated in vitro for their anti-proliferative activity against HePG-2, MCF-7, HCT-116, and PC-3 cell lines. Additionally, DNA binding affinity of the synthesized derivatives was investigated as a potential mechanism for the anticancer activity using DNA/methyl green assay and association constants assay. Compounds 19, 20, 21, 24 and 25 exhibited good activity against the four cancer cells comparable to that of doxorubicin. Interestingly, DNA binding assay results were in agreement with that of the cytotoxicity assays where the most potent anticancer compounds showed good DNA binding affinity comparable to that of doxorubicin and daunorubicin. Furthermore, a molecular docking of the tested compounds was carried out to investigate their binding pattern with the prospective target, DNA (PDB-code: 152d).     

Synthesis,antiproliferative activity and molecular docking of thiocolchicine urethanes

A number of naturally occurring compounds such as paclitaxel, vinblastine, combretastatin, and colchicine exert their therapeutic effect by changing the dynamics of tubulin and its polymer form, microtubules. The identification of tubulin as a potential target for anticancer drugs has led to extensive research followed by clinical development of numerous compounds from several families. In this paper we report on the design, synthesis and in vitro evaluation of a group of thiocolchicine derivatives, modified at ring-B, labelled here compounds 4–14. These compounds have been obtained in a simple reaction of 7-deacetyl-10-thiocolchicine 3 with eleven different alcohols in the presence of triphosgene. These novel agents have been checked for anti-proliferative activity against four human cancer cell lines and their mode of action has been confirmed as colchicine binding site inhibition (CBSI) using molecular docking. Molecular simulations provided rational tubulin binding models for the tested compounds. On the basis of in vitro tests, derivatives 4–8 and 14 demonstrated the highest potency against MCF-7, LoVo and A549 tumor cell lines (IC₅₀ values = 0.009–0.014 μM). They were more potent and characterized by a higher selectivity index than several standard chemotherapeutics including cisplatin and doxorubicin as well as unmodified colchicine. Further, studies revealed that colchicine and its several derivatives arrested MCF-7 cells in mitosis, while its selected derivatives caused microtubule depolymerization.     

Design,synthesis, biological and in silico evaluation of coumarin-hydrazone derivatives as tubulin targeted antiproliferative agents

Coumarin-based different series of hydrazone derivatives were synthesized and evaluated for anticancer activity against four different human cancer cell lines. The activity of the compounds were compared with doxorubicin as a standard drug and all the compounds exhibited good to moderate cytotoxicity with IC₅₀ values ranging from 6.07 to 60.45 µM against all the examined cancer cell lines. Based on the screening results, it was concluded that the compounds 12a and 18a were the most promising medicinal entities. In vitro tubulin polymerisation inhibition assay was performed for the compounds 12a and 18a and these two compounds displayed good potency when compared with colchicine as the standard drug. The interaction of these compounds with tubulin protein was also studied with the help of molecular docking technique using Discovery studio software. Furthermore, the molecular and ADMET properties of the compounds were computed with Osiris property software and PreADMET server. The compounds exhibited exciting in vitro and in silico results. Hence we propose that the compounds 12a and 18a could be developed as tubulin targeted potential antiproliferative agents.     

Triazolopyridazine derivatives: Synthesis,cytotoxic evaluation,c-Met kinase activity and molecular docking

Novel series of some triazolo[4,3-b]pyridazine derivatives were designed and synthesized. All the newly synthesized compounds were evaluated for their cytotoxic activity at 10⁻⁵ M concentration towards 60 cancer cell lines according to USA NCI protocol. Most of the synthesized compounds showed good activity against SR (leukemia) cell panel. The most active compounds, 2f and 4a were subjected for further evaluation at a five dose level screening and their efficacy for c-Met kinase inhibition was determined in vitro. Binding mode of these derivatives was explored via molecular docking.     

Synthesis of stable benzimidazole derivatives bearing pyrazole as anticancer and EGFR receptor inhibitors

A new series of benzimidazole linked pyrazole derivatives were synthesized by cyclocondensation reaction through one-pot multicomponent reaction in absolute ethanol. All the synthesized compounds were tested for their in vitro anticancer activities on five human cancer cell lines including MCF-7, HaCaT, MDA-MB231, A549 and HepG2. EGFR receptor inhibitory activities were carried out for all the compounds. Majority of the compounds showed potent antiproliferative activity against the tested cancer cell lines. Compound 5a showed the most effective activity against the lungs cancer cell lines (IC₅₀ = 2.2 µM) and EGFR binding (IC₅₀ = 0.97 µM) affinity as compared to other members of the series. Compound 5a inhibited growth of A549 cancer cells by inducing a strong G₂/M phase arrest. In addition, same compound inhibited growth of A549 cancer cells by inducing apoptosis. In molecular docking studies compound 5a was bound to the active pocket of the EGFR (PDB 1M17) with five key hydrogen bonds and two π-π interaction with binding energies ΔG = −34.581 Kcal/mol.     

Synthesis,cytotoxicity, and in vivo antitumor activity study of parthenolide semicarbazones and thiosemicarbazones

Parthenolide is an important sesquiterpene lactone with potent anticancer activities. In order to further improve its biological activity, a series of parthenolide semicarbazone or thiosemicarbazone derivatives was synthesized and evaluated for their anticancer activity. Derivatives were tested in vitro against 5 human tumor cell lines, and many of these showed higher cytotoxicity than parthenolide. Five compounds were further studied for their antitumor activity in mice. The in vivo result indicated that compound 4d showed both promising antitumor activity against mice colon tumor and small side effects on immune systems. The cell apoptosis and cell cycle distribution of compound 4d were also studied. Molecular docking studies revealed multiple interactions between 4d and NF-κB. Our findings demonstrate the potential of semicarbazones as a promising type of compounds with anticancer activity.     

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 and anti-tumor evaluation of B-ring substituted steroidal pyrazoline derivatives

The synthesis and anti-tumor activity screening of new steroidal derivatives (4–18) containing pharmacologically attractive pyrazoline moieties are performed. During in vitro anticancer evaluation, the newly synthesized compounds displayed moderate to good cytotoxicity on cervical and leukemia cancer cell lines. In addition these compounds were found to be nontoxic to normal cell (PBMCs) (IC₅₀ > 50 μM). The structure–activity relationship is also discussed. The most effective anticancer compound 9 was found to be active with IC₅₀ value of 10.6 μM. It demonstrated significant antiproliferative influence on Jurkat cell lines. The morphological changes and growth characteristics of HeLa cells treated with compound 4 were analyzed by means of SEM.     

Design,synthesis and biological evaluation of 2-(3,4-dimethoxyphenyl)-6 (1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridine analogues as antiproliferative agents

Two series of forty five novel 2-(3,4-dimethoxyphenyl)-6-(1,2,3,6-tetrahydropyridin-4-yl) imidazo[1,2-a]pyridine analogues (IPA 1–22, IPS 1–22 and IP-NH) have been designed, synthesized and structures confirmed by ¹H NMR, ¹³C NMR, mass spectrometry. Furthermore, single crystal was developed for IPS-13. All the final derived conjugates were evaluated for their in vitro antiproliferative activity against a panel of diverse cancer cell lines viz., A549 (lung cancer), HeLa (cervical cancer), B16F10 (melanoma) and found to show potent anticancer activity on the tested cell lines. Many of them showed the IC₅₀ values in the range 2.0–20.0 µM. The most active compounds (IPA 5,6,8,9,12,16,17,19 and IPS 7,8,9,22) from IPA and IPS series were screened to determine their cytotoxicity on HEK-293 (human embryonic kidney) normal cell line and were found to be nontoxic to normal human cells. The molecular interactions of the derivatised conjugates were also supported by molecular docking simulations. These derivatives may serve as lead structures for development of novel potential anticancer drug candidates.     

Design,synthesis, and biological evaluation of 4-((6,7-dimethoxyquinoline-4-yl)oxy)aniline derivatives as FLT3 inhibitors for the treatment of acute myeloid leukemia

FMS-like tyrosine kinase 3 (FLT3) was an important therapeutic target in acute myeloid leukemia (AML). We synthesized two series of 4-((6,7-dimethoxyquinoline-4-yl)oxy)aniline derivatives possessing the semicarbazide moiety and 2,2,2-trifluoro-N,N′-dimethylacetamide moiety as the linker. The cell proliferation assay in vitro against HL-60 and MV4-11 cell lines demonstrated that most series I compounds containing semicarbazide moiety had more potent than Cabozantinib. Furthermore, the enzyme assay showed that compound 12c and 12g were potent FLT3 inhibitors with IC₅₀ values of 312 nM and 384 nM, respectively. Following that, molecular docking analysis was also performed to determine possible binding mode between FLT3 and the target compound.     

New imidazoquinoxaline derivatives: Synthesis,biological evaluation on melanoma,effect on tubulin polymerization and structure–activity relationships

Microtubules are considered as important targets of anticancer therapy. EAPB0503 and its structural imidazo[1,2-a]quinoxaline derivatives are major microtubule-interfering agents with potent anticancer activity. In this study, the synthesis of several new derivatives of EAPB0503 is described, and the anticancer efficacy of 13 novel derivatives on A375 human melanoma cell line is reported. All new compounds show significant antiproliferative activity with IC₅₀ in the range of 0.077–122 μM against human melanoma cell line (A375). Direct inhibition of tubulin polymerization assay in vitro is also assessed. Results show that compounds 6b, 6e, 6g, and EAPB0503 highly inhibit tubulin polymerization with percentages of inhibition of 99%, 98%, 90%, and 84% respectively. Structure–activity relationship studies within the series are also discussed in line with molecular docking studies into the colchicine-binding site of tubulin.     

Design and synthesis of new phthalazine-based derivatives as potential EGFR inhibitors for the treatment of hepatocellular carcinoma

Searching for new leads in the battle of cancer will never ends, we herein disclose the design and synthesis of new phthalazine derivatives and their in vitro and in vivo testing for their antiproliferative activity. Phthalazine was selected as a privilege moiety that is incorporated in a big number of anticancer drugs in clinical use or that are still under clinical or preclinical studies. We utilized the drug extension strategy to tailor the designed compounds to fit the EGFR hydrophobic sub pocket and cleft region. The designed phthalazine derivatives was synthesized by linking phthalazine moiety with 1,3,4-oxadiazole-thione and 1,2,4-triazole-thione. Alkylation and glycosylation of the new heterocyclic systems were successfully performed to be used in the drug extension. Coupling of some phthalazine derivatives with different amino acids was also performed to improve the drug selectivity.The synthesized compounds were tested for their antiproliferative activity against cancer cells both in vivo and in vitro. The in vitro activity against hepatocellular carcinoma (HepG2 cell line) ranged from 5.7 µg/mL to 43.4 µg/mL. Compounds 31a and 16 were the most active with an IC₅₀ 5.7 µg/mL and 7.09 µg/mL, respectively compared to the standard compound doxorubicin (4.0 µg/mL). In vivo, compounds 10 and 16 showed IC₅₀ values 7.25 μg/mL and 7.5 μg/mL, respectively compared to the standard compound cisplatin (IC₅₀ 9.0 μg/mL). In silico, testing of the phthalazine derivatives showed that they are good inhibitors for EGFR. The docking studies substantiated compounds 4, 10, 16 and 31a as new lead compounds and identified Arg841 as a key residue in the cleft region for binding stronger inhibitors.     

Modulation of PPAR subtype selectivity. Part 2: Transforming PPARα/γ dual agonist into α selective PPAR agonist through bioisosteric modification

A novel series of oxime containing benzyl-1,3-dioxane-r-2-carboxylic acid derivatives (6a-k) were designed as selective PPARα agonists, through bioisosteric modification in the lipophilic tail region of PPARα/γ dual agonist. Some of the test compounds (6a, 6b, 6c and 6f) showed high selectivity towards PPARα over PPARγ in vitro. Further, highly potent and selective PPARα agonist 6c exhibited significant antihyperglycemic and antihyperlipidemic activity in vivo, along with its improved pharmacokinetic profile. Favorable in-silico interaction of 6c with PPARα binding pocket correlate its in vitro selectivity profile toward PPARα over PPARγ. Together, these results confirm discovery of novel series of oxime based selective PPARα agonists for the safe and effective treatment of various metabolic disorders.     

Design,synthesis and biological evaluation of novel chromeno[4,3-c]pyrazol-4(2H)-one derivates containing sulfonamido as potential PI3Kα inhibitors

A series of novel chromeno[4,3-c]pyrazol-4(2H)-one derivates contained sulfonamido were designed and synthesized, and their anticancer effects in vitro was evaluated to develop some new PI3Kα inhibitors. Most of desired compounds exhibited the better antiproliferative activities against four cancer cell lines than that of LY294002. Out of them, compound 4o displayed the potent antiproliferative activity and high selectivity against the PI3Kα protein and it can induce apoptosis of HCT116 in a dose-dependent manner. Western blot assay indicated that compound 4o obviously down-regulated expression of p-Akt (S473). Molecular docking was performed to clarify the possible binding mode between compound 4o and PI3Kα. All these results indicated that compound 4o could be a potential inhibitor of PI3Kα.     

Synthesis,biological evaluation and molecular docking studies of aminochalcone derivatives as potential anticancer agents by targeting tubulin colchicine binding site

A series of aminochalcone derivatives have been synthesized, characterized by HRMS, ¹H NMR and ¹³C NMR and evaluated for their antiproliferative activity against HepG2 and HCT116 human cancer cell lines. The most of new synthesized compounds displayed moderate to potent antiproliferative activity against test cancer cell lines. Among the derivatives, compound 4 displayed potent inhibitory activity with IC₅₀ values ranged from 0.018 to 5.33 μM against all tested cancer cell lines including drug resistant HCT-8/T. Furthermore, this compound showed low cytotoxicity on normal human cell lines (LO2). The in vitro tubulin polymerization assay showed that compound 4 inhibited tubulin assembly in a concentration-dependent manner with IC₅₀ value of 7.1 μM, when compared to standard colchicine (IC₅₀ = 9.0 μM). Further biological evaluations revealed that compound 4 was able to arrest the cell cycle in G2/M phase. Molecular docking study demonstrated the interaction of compound 4 at the colchicine binding site of tubulin. All the results indicated that compound 4 is a promising inhibitor of tubulin polymerization for the treatment of cancer.     

Synthesis and biological evaluation of Schizandrin derivatives as tubulin polymerization inhibitors

A series of oxime ester-derivatives were prepared by utilizing the schizandrin (1), a major compound isolated from Schisandra grandiflora, which is deployed in different traditional system of medicine. The in vitro antiproliferative activities of the synthesized compounds were assessed against a selected panel of human cancer cell lines (A549, RKO P3, DU145 and Hela) and normal cell (HEK293). Several of these derivatives were found more potent in comparison to parent compound, schizandrin (1). Particularly, 4a and 4b demonstrated potent activity against DU-145 and RKOP3 cell lines with IC₅₀ values of 3.42 µM and 3.35 µM respectively. To characterize the molecular mechanisms involved in antitumoral activity, these two compounds, 4a and 4b were selected for further studies. Cell cycle analysis revealed that both the compounds were able to induce apoptosis and cell cycle arrest at G₀/G₁ phase. To know the extent of apoptosis in DU145 and RKOP3 cell lines, Annexin V-FITC were performed. Moreover, the tubulin polymerization assay indicated that 4a and 4b exhibits potent inhibitory effect on the tubulin assembly. Molecular docking studies and competitive binding assay also indicated that 4a and 4b effectively bind at the colchicine binding site of the tubulin.     

Design,synthesis and evaluation of novel sophoridinic imine derivatives containing conjugated planar structure as potent anticancer agents

Based on our previous study and the binding mode of camptothecin with Topo I, a series of novel sophoridine imine derivatives containing conjugated planar structure were designed, synthesized and tested for their in vitro anticancer activity. The results showed that most of the derivatives displayed potent activity. In particular, compounds 10b exhibited excellent anti-proliferative activities with IC₅₀ 5.7?µM and 8.5?µM against HepG-2 and HeLa cell lines, respectively. Molecular docking studies revealed that the introduction of conjugated planar structure could form π-π stacking interaction with DNA, leading to the improvement of biological activity. Its mode of action was to inhibit the activity of DNA Topo I, followed by the G0/G1 phase arrest. This work provides a theoretical basis for structural optimizations and exploring anticancer pathways of this kind of compound and 10b could emerge as promising lead compounds for the development of novel Topo I inhibitors.     

Targeting hepatocellular carcinoma: Synthesis of new pyrazole-based derivatives,biological evaluation,DNA binding,and molecular modeling studies

A new series of pyrazole derivatives was prepared in this work, including pyrazolopyrimidines, pyrazolotriazines, pyrazolylthienopyridines, and 2-(pyrazolylamino)thiazol-4-ones, utilizing 3-amino-5-methyl-1H-pyrazole as a synthetic precursor. Their in vitro anticancer activity was tested on hepatocellular carcinoma cell line, HepG2. The results revealed that the pyrazolylhydrazonoyl cyanide 8, the pyrazolopyrimidine 3, and the pyrazolylaminothiazolone 17 were the most active with IC₅₀ values of 2, 7, and 7 µM respectively in comparison with 5.5 µM for cisplatin as a reference drug. Interestingly, all the synthesized compounds showed higher selectivity index than cisplatin. DNA binding assay was also carried out for the synthesized compounds to rationalize their mechanism of action. Molecular modeling studies, including docking into DNA minor groove, flexible alignment, and surface mapping, were conducted. Results obtained proved the superior DNA-binding affinity of the most active anticancer compounds.