A potential CARB-pharmacophore for antineoplastic activity: Part 1

Diverse functionalized representatives of various classes of sugars, such as thio-, anhydro-, and sulfamido-sugars and myo-inositol oxide, were synthesized and assessed for cytotoxicity against human cancer cell lines (A549, LoVo, MCF-7 and HeLa). The inositol oxide (4) was more active against MCF-7 cells (i.e., an estrogen-dependent breast cancer line), whereas all 3 sulfur-containing compounds showed strongest activity against A549 cells (i.e., a lung adenocarcinoma line). We propose to use a concept of functional ‘CARB-pharmacophores’ when evaluating a potential for the compounds’ general antineoplastic activity. Future studies will determine the reasons for cell-type specificity of these compounds. The thio-sugar motif appears to be a promising lead for future developments.     

Synthesis and cytotoxicity evaluation of highly functionalized pyranochromenes and pyranopyrans

A series of fluorinated tetrahydropyrano[3,2-c]chromenes and dihydropyrano[3,2-b]pyran derivatives have been synthesized and their in vitro cytotoxic activities have been determined in cervical cancer cell line (HeLa), human breast adenocarcinoma cell line (MDA-MB-231 and MCF-7) and human alveolar adenocarcinoma cell line (A549). Compounds 4g, 4k, 4p showed a very potent activity against MDA-MB-231, and 4c, 4p showed promising activity against MCF-7, while compounds 4c, 4g, 4p showed moderate activity against HeLa.     

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.     

Synthesis and biological evaluation of imidazo[2,1-b]thiazole-benzimidazole conjugates as microtubule-targeting agents

A series of imidazo[2,1-b]thiazole-benzimidazole conjugates were synthesized and evaluated for their antiproliferative activity against four human cancer cell lines i.e.; HeLa (cervical), A549 (lung), MCF-7 (breast) and DU-145 (prostate) along with normal HEK-293 cell line. Amongst them, conjugate 6d displayed significant cytotoxicity against human lung cancer cell line, A549 with IC₅₀ value 1.08 µM. Further, cell cycle analysis revealed that this compound arrested the cell cycle at G2/M phase in A549 cells. Furthermore, the tubulin polymerization assay results suggest that this conjugate (6d) exhibits significant inhibitory effect on the tubulin assembly with an IC50 value of 1.68 µM. Moreover, the apoptotic inducing properties of compound 6d was confirmed by Hoechst staining, measurement of mitochondrial membrane potential (ΔΨm) and annexin V-FITC assay. Further, molecular docking studies revealed that compound 6d occupied the colchicine binding site.     

Incrassamarin A–D: Four new 4-substituted coumarins from Calophyllum incrassatum and their biological activities

Four new 4-substituted coumarins, incrassamarin A (1), B (2), C (3) and D (4) with (7S,8S)-7,8-dihydro-5-hydroxy-7,8-dimethyl-4-propyl-2H,6H-benzo[1,2-b;5,4-b’]dipyran-2,6-dione (5), friedelin, carpachromene, amentoflavone, epiafzelechin and L-quercitrin were isolated from the barks and leaves of Calophyllum incrassatum (Guttiferae). The compounds were isolated and purified by size-exclusion recycling HPLC and column chromatographic techniques. The structures of the compounds were determined by spectroscopic means. The compounds were tested for their cytotoxic activity towards MCF-7 and A-549 cell lines and α-glucosidase enzymatic inhibitory activity. Compound (1) displayed cytotoxic activity against A-549 cell lines with IC₅₀ 87.71 μg/mL and showed inhibition towards α-glucosidase enzymatic activity with IC₅₀ 93.25 μM. This is the first report on the isolation of phytochemicals from the barks and leaves of C. incrassatum and their bioactivities.     

Constituents of the leaves of Pseuderanthemum carruthersii (Seem.) Guill. var. atropurpureum (Bull.) Fosb.

A new iridoid, 5β,6β-dihydroxyantirrhide (1) was isolated from the dried leaves of Pseuderanthemum carruthersii (Seem.) Guill. var. atropurpureum (Bull.) Fosb. (Acanthaceae), together with 13 known compounds, including two iridoids, linarioside and antirrhinoside; five phenylethanoids, echipuroside A, verbascoside, isoverbascoside, isomartynoside and osmanthuside B; and six flavonoids, luteolin 7-O-β-d-glucopyranoside, luteolin 7-O-rutinoside, apigenin 7-O-rutinoside, apigenin 6-C-α-l-arabinopyranosyl–8-C-β-l-arabinopyranoside, apigenin 6,8-di-C-α-l-arabinopyranoside and apigenin 6-C-β-d-xylopyranosyl–8-C-α-l-arabinopyranoside. Their chemical structures were elucidated by 1D and 2D NMR as well as HR-ESI-MS spectroscopic analysis. Some purified compounds were evaluated the acetylcholinesterase inhibition and cytotoxic activities against the HeLa cervical cancer cell line and the MCF-7 breast cancer cell line at the concentration of 100 μg/mL. Luteolin 7-O-β-d-glucopyranoside exhibited cytotoxic activities against both the HeLa cervical cancer cell line and the MCF-7 breast cancer cell line. Verbascoside and isoverbascoside showed strong cytotoxic activity against the MCF-7 breast cancer cell line. The tested compounds showed the AChE inhibitory activity fairly weak.     

Two new lactones from whole herbs of Patrinia villosa Juss

Chemical investigation of 70% EtOH exact of Patrinia villosa Juss. led to the isolation, purification and identification of two new lactones (1-2) along with twelve known compounds (3-14). Their structures were established by comprehensive spectroscopic analyses. All compounds were evaluated for their cytotoxic activities against A549, HepG2, Hep3 B and MCF-7 cancer cell lines. Compounds 1, 8, 10, 11 and 12 displayed weak cytotoxic activities against MCF-7 cell line. In addition, compounds 1, 2, 8, 10, 11 and 12 were also tested their antimicrobial activities against Micrococcus luteus. Unfortunately, these compounds were found to be inactive.     

Synthesis and biological evaluation of benzo[b]furo[3,4-e][1,4]diazepin-1-one derivatives as anti-cancer agents

A new series of novel Podophyllotoxin-like benzo[b]furo[3,4-e][1,4]diazepin-1-ones possessing structural elements of 4-aza-2,3-didehydropodophyllotoxins with central diazepine ring was designed and synthesized as anti-cancer agents. In initial assessment, the cytotoxic activity of the synthesized compounds was evaluated against three cancer cell lines including MCF-7, PC3 and B16-F10 employing the MTT assay. Some of compounds (12h, 13a, 13c and 14b) showed significant cytotoxic activity. So, we investigated the cytotoxicity of compounds 12h, 13a, 13c and 14b, along with podophyllotoxin as the reference drug in different cancer cell lines including A549, A2780, DU145, HeLa, and normal Huvec cell line. Among these four compounds, 13c showed promising antiproliferative activity against all cancer cells stronger than the other compounds and comparable to reference drug podophyllotoxin in some cancer cells. All these four compounds did not show significant cytotoxicity on normal Huvec cell line. The flow cytometry analysis of the MCF-7, PC3 and A2780 human cancer cell lines treated with 13c showed that 13c, induced apoptosis in the MCF-7, PC3 and A2780 human cancer cell lines, which is in good agreement to its cytotoxic activity as well. Compound 13c did not show significant influence on tubulin assembly and exert its cytotoxic effects via induction of apoptosis and has potent and selective cytotoxic effects in cancer cells.     

Synthesis of DNA interactive C3-trans-cinnamide linked β-carboline conjugates as potential cytotoxic and DNA topoisomerase I inhibitors

A series of new C3-trans-cinnamide linked β-carboline conjugates has been synthesized by coupling between various β-carboline amines and substituted cinnamic acids. Evaluation of their anti-proliferative activity against a panel of selected human cancer cell lines such as A549 (lung cancer), MCF-7 (breast cancer), B16 (melanoma), HeLa (cervical cancer) and a normal cell line NIH3T3 (mouse embryonic fibroblast cell line), suggested that the newly designed conjugates are considerably active against all the tested cancer cell lines with IC₅₀ values 13–45?nM. Moreover, the conjugates 8v and 8x were the most active against MCF-7 cells (14.05?nM and 13.84?nM respectively) and also even potent on other cell lines tested. Further, detailed investigations such as cell cycle analysis, apoptosis induction study, topoisomerase I inhibition assay, DNA binding affinity and docking studies revealed that these new conjugates are DNA interactive topoisomerase I inhibitors.     

Design and synthesis of 4β-Acetamidobenzofuranone-podophyllotoxin hybrids and their anti-cancer evaluation

A new series of amide derivatives of 4β-Acetamidobenzofuranone-podophyllotoxin hybrids (14a–g) were synthesized and their chemical structures were confirmed by ¹H, ¹³C NMR and mass spectral data. Further, all the synthesized Acetamidobenzofuranone-podophyllotoxin hybrids were evaluated for in vitro cytotoxic activity against a panel of four human cancer cell lines i.e., human breast (MCF-7, MDA MB-231), lung (A549), and prostrate (DU-145). Among benzofuranone-podophyllotoxin hybrid compounds, 14b and 14e were exhibited more potent activity than standard drug and 14c and 14f were showed anticancer activity equivalent to etoposide.     

Design,synthesis and biological evaluation of six dinuclear platinum(II) complexes

Six dinuclear platinum(II) complexes with a chiral tetradentate ligand, (1R,1′R,2R,2′R)-N¹,N^1′-(1,4-phenylenebis(methylene))dicyclohexane-1,2-diamine, have been designed, synthesized and characterized. In vitro cytotoxicity evaluation of these metal complexes against human A549, HCT-116, MCF-7 and HepG-2 cell lines have been carried out. All compounds showed antitumor activity to HepG-2, HCT-116 and A549. Particularly, compounds A1 and A2 exhibited significant better activity than other four compounds and A2 even showed comparable cytotoxicity to cisplatin against HepG-2 cell line.     

Two new flavonol derivatives from the whole plants of Centella asiatica and their cytotoxic activities

Centella asiatica is well known as an important medicinal plant because of its various pharmacological effects. However, most investigations on C. asiatica focused on the pharmacological activity of its extract or asiatic acid. In the present work, we aimed to explore the bioactive compounds of the whole plants of C. asiatica. As a result, seven compounds including two new flavonol derivates named 4′-hydroxyl-7-methoxyl-6-prenyl-3-O-trans-p-coumaroyl-flavonol (1) and (2R,3R,2″S)-3-furanoyl-brosimacutin E (2), and five known compounds (3-7) were isolated. Their chemical structures were elucidated on the basis of spectroscopic analyses. All the isolates were evaluated for in vitro cytotoxic effects on four human cancer cells including A549, HepG2, SGC-7901 and MCF-7. Among them, compounds 1 and 2 exhibited higher cytotoxic activities on HepG2 and SGC-7901 cells compared with 3-7. And compound 2 showed potential cytotoxic activities on HepG2 and SGC-7901 cells with IC₅₀ values of 4.52 and 7.03 μM, respectively.     

Synthesis and biological evaluation of tetracyclic fluoroquinolones as antibacterial and anticancer agents

A simple and efficient synthesis of 6-fluoro-4-oxopyrido[2,3-a]carbazole-3-carboxylic acids (13a–e) and a structurally related 6-fluoro-4-oxothieno[2′,3′:4,5]pyrrolo[3,2-h]quinoline (13f) was achieved via Stille arylation of 7-chloro-6-fluoro-8-nitro-4-oxoquinoline-3-carboxylate and a subsequent microwave-assisted phosphite-mediated Cadogan reaction. The new compounds were tested for their in vitro antimicrobial and antiproliferative activity. The ability of 13a–f to inhibit the activity of DNA gyrase and topoisomerase IV was also investigated. The thieno isostere (13f) emerged as the most active antibacterial, while the 9-fluoro derivative (13e) was the most potent against multidrug-resistant staphylococci. Compounds 13a, 13c–f displayed growth inhibition against MCF-7 breast tumor and A549 non-small cell lung cancer cells coupled with an absence of cytotoxicity toward normal human-derm fibroblasts (HuDe). Compound 13e was the most active anticancer against MCF-7 cells, with greater potency than ellipticine (IC₅₀ 0.8 and 1.6 μM, respectively). The most active compounds in this series show promise as dual acting anticancer and antibacterial chemotherapeutics.     

Artemisinin-indole and artemisinin-imidazole hybrids: Synthesis,cytotoxic evaluation and reversal effects on multidrug resistance in MCF-7/ADR cells

A series of artemisinin derivatives with MDR reversal activity were designed and synthesized. All hybrids were screened to anticancer activities against four human cancer cell lines (A549, MCF-7, HepG-2, MDA-MB-231) and normal human hepatic cell (L02) in vitro. Most of the new compounds showed higher anticancer activities than artemisinin, among which compounds 11a and 11c displayed superior potency with IC₅₀ 6.78?μM and 5.25?μM against MCF-7, respectively. The further research indicated that the most potent 11c induced cell cycle arrest at G2 phase in MCF-7. Additionally, compound 11c showed remarkable MDR reversal activity which reversed adriamycin against MCF-7/ADR cells with IC₅₀ 0.76?μM.     

Discovery of thinopyrimidine-triazole conjugates as c-Met targeting and apoptosis inducing agents

Five series of N-methylpicolinamide moiety and thienopyrimidine moiety bearing triazole (21–26, 27–34, 35–41, 42–47 and 48–54) were designed and synthesized. And all the target compounds were evaluated for the IC₅₀ values against three cancer cell lines (A549, HepG2 and MCF-7) and some selected compounds (43, 49 and 52) were further evaluated for the activity against c-Met, Flt-3, VEGFR-2, c-Kit and EGFR kinases. Moreover, SARs and docking studies indicated that thieno[3,2-d]pyrimidine bearing triazole moiety was privileged structure for the activity. Especially, the Cl atom on the 4-C position of aryl group showed the best activity. The most promising compound 49 showed 3.7–5.4-fold more activity than the lead drug Foretinib against A549, HepG2 and MCF-7 cell lines, with the IC₅₀ values of 0.9 ± 0.1 µM, 0.5 ± 0.1 µM and 1.1 ± 0.2 µM, respectively. And The experiments of enzyme-based showed that 49 inhibitor the c-Met selectively, with the IC₅₀ values of 16 nM, which showed equal activity to Foretinib (14 nM). What’s more, According to the result of AO single staining and Annexin V/PI staining, it's claimed that the 49 could induce late apoptosis of HepG2 cells and by a concentration-dependent manner.     

New amide linked dimeric 1,2,3-triazoles bearing aryloxy scaffolds as a potent antiproliferative agents and EGFR tyrosine kinase phosphorylation inhibitors

A search for potent antiproliferative agents has prompted to design and synthesize aryloxy bridged and amide linked dimeric 1,2,3-triazoles (7a–j) by using 1,3-dipolar cycloaddition reaction between 2-azido-N-phenylacetamides (4a–e) and bis(prop-2-yn-1-yloxy)benzenes (6a–b) via copper (I)-catalyzed click chemistry approach with good to excellent yields. All the newly synthesized compounds have been screened for their in vitro antiproliferative activities against two human cancer cell lines. The compounds 7d, 7e, 7h, 7i and 7j have revealed promising antiproliferative activity against human breast cancer cell line (MCF-7), whereas, the compounds 7a, 7b, 7c, 7i and 7j were observed as potent antiproliferative agents against human lung cancer cell line (A-549). The active compounds against MCF-7 have been also analysed for their mechanism of action by the enzymatic study, which shows that the compounds 7d, 7h and 7j were acts as active EGFR tyrosine kinase phosphorylation inhibitors. In support to this biological study, the molecular docking as well as in silico ADME properties of all the newly synthesized hybrids were predicted.     

3,4-Dihydroisocoumarin derivatives from the marine-derived fungus Paraconiothyrium sporulosum YK-03

Two new 3,4-dihydroisocoumarin derivatives, (3S, 4S)-4,5-dihydroxymellein (1) and R-(−)-mellein-8-O-β-d-glucopyranoside (2), together with six known analogs (3–8) were isolated from the marine-derived fungus Paraconiothyrium sporulosum YK-03. Their structures including absolute configurations were elucidated by extensive spectroscopic methods in combination with computational electronic circular dichroism (ECD) method, optical rotation analysis and monosaccharide composition analysis using HPLC with optical rotation detector. All of them were evaluated for their cytotoxic activities against the human cancer cell lines A549 and MCF-7.     

Synthesis of 1,2,4-triazole-linked urea/thiourea conjugates as cytotoxic and apoptosis inducing agents

A new series of 1,2,4-triazole-linked urea and thiourea conjugates have been synthesized and evaluated for their in vitro cytotoxicity against selected human cancer cell lines namely, breast (MCF-7, MDA-MB-231), lung (A549) prostate (DU145) and one mouse melanoma (B16-F10) cell line and compared with reference drug. The compound 5t showed significant cytotoxicity on MCF-7 breast cancer cell line with a IC₅₀ value of 7.22?±?0.47?µM among all the tested compounds. Notably, induction of apoptosis by compound 5t on MCF-7 cells was evaluated using different staining techniques such as acridine orange/ethidium bromide (AO/EB), annexin V-FITC/PI, and DAPI. Further, clonogenic assay indicates the inhibition of colony formation on MCF-7 cells by compound 5t. Moreover, the flow-cytometric analysis also revealed that compound 5t caused the arrest of cells at G0/G1 phase of cell cycle. In addition, the compounds when tested on normal human cells (L-132) were found to be safer with low cytotoxicity profile.     

Withanolides from Withania aristata and their cytotoxic activity

Seven new withanolides (1-7), along with three known ones (8-10), were isolated from the leaves of Withania aristata. Their structures were elucidated on the basis of spectroscopic analysis, including 2D NMR experiments and spectrometric techniques, and the absolute configuration of 1 and 2 was established by CD analysis. In the search for new cytotoxic compounds from Withania species, the isolated compounds 1-9, along with two derivatives, were assayed for their cytotoxicity against HeLa, MCF-7 and A-549 human tumor cell lines. Derivative (4S,20R,22R)-27-acetoxy-4-p-bromobenzoyloxy-1-oxo-witha-2,5,16,24-tetraenolide (13) showed cytotoxicity against all the cell lines assayed with IC₅₀ values ranging from 2.8 to 3.6 μM, and (4S,20R,22R)-4,27-diacetoxy-4-hydroxy-1-oxo-witha-2,5,16,24-tetraenolide (12) exhibited an IC₅₀ value of 5.4 μM on the MCF-7 cell line.     

Natural product inspired allicin analogs as novel anti-cancer agents

A series of novel analogs of Allicin (S-allyl prop-2-ene-1-sulfinothioate) present in garlic has been synthesized in high yield. Synthesized 23 compounds were evaluated against different breast cancer cells (MDA-MB-468 and MCF-7) and non-cancer cells (WI38). Four compounds (3f, 3h, 3m and 3u) showed significant cytotoxicity against cancer cells whereas nontoxic to the normal cells. Based on the LD₅₀ values and selectivity index (SI), compound 3h (S-p-methoxybenzyl (p-methoxyphenyl)methanesulfinothioate) was considered as most promising anticancer agent amongst the above three compounds. Further bio-chemical studies confirmed that compound 3h promotes ROS generation, changes in mitochondrial permeability transition and induced caspase mediated DNA damage and apoptosis.