Design and synthesis of aminocoumarin derivatives as DPP-IV inhibitors and anticancer agents

DPP-IV “a moonlighting protein” has immerged as promising pathway to control Type 2 diabetes as well as found to play key role in earlier stages of cancer. Here we have reported design, synthesis and applications of aminocoumarin derivatives as DPP-IV inhibitors. Compounds have been synthesized and studied for their DPP-IV inhibition activity. Three compounds have shown moderate inhibition at 100 µM concentration. All compounds were also screened for their anticancer activity against A549 (Lung cancer cell line), MCF-7 (Breast cancer cell line) using MTT assay. One of the compounds has shown very good anticancer activity with IC₅₀ value 24 ± 0.1 nM against A549 cell line.     

Design, synthesis and biological evaluation of novel quinazoline derivatives as potential anti-cancer agents

Twenty-two quinazoline derivatives have been synthesised and examined for their anti-tumour activity against three tumour cell lines, namely human breast cancer cell line (MCF-7), human cervical cancer cell line (HeLa) and human hepatoma cell line (HepG2). Twelve of the tested compounds have shown promising anti-tumour activity with an IC(50) range of 5.0-9.7 μg/mL. Regarding the spectrum of activity, five compounds exhibited interesting anti-proliferative properties against the three tested cell lines comparable to the reference drug (dasatinib).     

Design,synthesis and biological evaluation of novel quinazoline derivatives as potential anti-cancer agents

Twenty-two quinazoline derivatives have been synthesised and examined for their anti-tumour activity against three tumour cell lines, namely human breast cancer cell line (MCF-7), human cervical cancer cell line (HeLa) and human hepatoma cell line (HepG2). Twelve of the tested compounds have shown promising anti-tumour activity with an IC₅₀ range of 5.0–9.7 µg/mL. Regarding the spectrum of activity, five compounds exhibited interesting anti-proliferative properties against the three tested cell lines comparable to the reference drug (dasatinib).     

Target fishing and docking studies of the novel derivatives of aryl-aminopyridines with potential anticancer activity

A set of 16 previously synthesized aryl-aminopyridine and aryl-aminoquinoline derivatives have been evaluated for cytotoxic activity against three cancer cell lines (human cervical cancer-HeLa; human chronic myeloid leukemia-K562; human melanoma-Fem-x) and two types of normal peripheral blood mononuclear cells, with and without phytohemaglutinin (PBMC-PHA; PBMC+PHA). Twelve of the studied compounds showed moderate cytotoxicity, with selectivity against K562 but not the remaining two cancer cell lines. Four compounds were not active in cytotoxicity assays, presumably due to high predicted lipophilicity and low solubility. To rationalize the observed cytotoxic effects, structure-based virtual screening was carried out against a pool of potential targets constructed using the inverse docking program Tarfisdock and bibliographical references. The putative targets were identified on the basis of the best correlation between docking scores and in vitro cytotoxicity. It is proposed that the mechanism of action of the studied aminopyridines involves the disruption of signaling pathways and cancer cell cycle through the inhibition of cyclin-dependent kinases and several tyrosine kinases, namely Bcr-Abl kinase and KIT receptor kinase. The obtained results can guide further structural modifications of the studied compounds aimed at developing selective agents targeting proteins involved in cancer cell survival and proliferation.     

Biological evaluation of new antitumor taxoids: Alteration of substitution at the C-7 and C-10 of docetaxel

A series of new docetaxol analogues have been designed and synthesized. And their cytotoxicities against cancer cells have been evaluated by MTT method. Most of these compounds showed selective inhibitions on human cancer cell lines. Among them, compound 8 exhibited higher inhibitory activity than Paclitaxel (Taxol) against several cancer cell lines. This work indicated that appropriate modification at C-7 and C-10 of docetaxel might be a promising approach for this unique class of anticancer compounds.     

Synthesis and antitumor activity of 1,2,4-triazoles having 1,4-benzodioxan fragment as a novel class of potent methionine aminopeptidase type II inhibitors

A series of 1,2,4-triazole derivatives containing 1,4-benzodioxan (5a-5q) have been designed, synthesized, structurally determined, and their biological activities were evaluated as potential MetAP2 inhibitors. All the synthesized compounds were first reported. Among the compounds, compound 5k showed the most potent biological activity against HEPG2 cancer cell line (IC(50)=0.81 μM for HEPG2 and IC(50)=0.93 μM for MetAP2), which was comparable to the positive control. Docking simulation by positioning compound 5k into the MetAP2 structure active site was performed to explore the possible binding model. The results of apoptosis and Western-blot assay demonstrated that compound 5k possessed good antitumor activity against HEPG2 cancer cell line. Therefore, compound 5k with potent inhibitory activity in tumor growth inhibition may be a potential antitumor agent against HEPG2 cancer cell.     

Studies on activities, cell uptake and DNA binding of four trans-planaramineplatinum(II) complexes of the form: trans-PtL(NH3)Cl2, where L=2-hydroxypyridine, imidazole, 3-hydroxypyridine and imidazo(1,2-alpha)pyridine

Four trans-planaramineplatinum(II) complexes code named YH9, YH10, YH11 and YH12 each of the form trans-PtL(NH(3))Cl(2), where L=2-hydroxypyridine and 3-hydroxypyridine, imidazole, and imidazo(1,2-alpha)pyridine for YH9, YH10, YH11 and YH12, respectively, have been synthesized and the activity of the compounds against human cancer cell lines, cell uptake, DNA-binding and nature of interaction with pBR322 plasmid DNA have been studied. The compound having imidazo(1,2-alpha)pyridine ligand as one the carrier ligands in the trans-configuration is found to be significantly more active than cis-platin against ovarian A2780(cisR) cancer cell line corresponding with higher Pt-DNA binding. All other compounds have resistance factors less than that for cis-platin in the A2780 and A2780(cisR) cell lines. A greater prevention of BamH1 digestion with increasing concentration of the compounds indicates that as the compounds bind with nucleobases in DNA, the DNA conformation is changed sufficiently so as to prevent BamH1 digestion at the specific GG site. Gel electrophoresis results also indicate that as the compounds bind to DNA, unwinding of supercoiled form I DNA takes place to change it from the negatively supercoiled form I through relaxed circular form I to the positively supercoiled form I.     

Studies on quinones. Part 42: Synthesis of furylquinone and hydroquinones with antiproliferative activity against human tumor cell lines

The preparation of furyl-1,4-quinone and hydroquinones by reaction of 2-furaldehyde N,N-dimethylhydrazone with benzo- and naphthoquinones is reported. Access to furylnaphthoquinones from unactivated quinones requires acid-induced conditions, however oxidative coupling reactions of activated quinones proceed under neutral conditions. The in vitro cytotoxic activity of the prepared compounds against a panel of three human cancer cell lines has been studied. Most of the furyl-1,4-quinones exhibited good antiproliferative activity (GI(50)=6.5-33.5microm) against the MCF-7, NCI-H460, and SF-268 (CNS cancer) cell lines chosen for testing.     

Synthesis and hypoxic-cytotoxic activity of some 3-amino-1,2,4-benzotriazine-1,4-dioxide derivatives

A series of 3-amino-1,2,4-benzotriazine-1,4-dioxide derivatives 1 have been synthesized and evaluated for their cytotoxic activity in vitro against human leukemia cell lines: Molt-4, K562, HL60, human liver cancer cell Hep-G2, human prostate cancer cell PC-3 in hypoxia. Most of the compounds showed more potent activity than TPZ. Compounds 1i and 1m displayed encouraging superior activity against Molt-4 and HL-60 cell lines. Three potential derivatives received the test of the activity in hypoxia and in normoxia against Molt-4 and HL-60 cell lines and showed obvious hypoxia selectivity. Further mechanism study revealed that the cytotoxic activities of compounds 1i and 1k in Molt-4 cells might be mediated by modulation of p53 protein expression and mitochondrial membrane potential (DeltaPsi(m)).     

Synthesis and biological evaluation of novel triazoles and isoxazoles linked 2-phenyl benzothiazole as potential anticancer agents

A new series of isoxazoles and triazoles linked 2-phenyl benzothiazole were synthesized and evaluated for their anticancer activity. These compounds have been tested for their cytotoxicity three cancer cell lines. Among the compounds tested, compound 5d showed good cytotoxicity against Colo-205 and A549 cells in comparison to standard control PMX 610(1). Further compound 5d has been tested for its apoptotic activity and its inhibitory activity against caspase and PARP proteins. Hence this compound has the potential that it can be selected for further biological studies.     

Synthesis and biological activity of new arenediyne-linked isoxazolidines

Arenediyne–isoxazolidine conjugates have been synthesized as a new scaffold for the development of bioactive mimics. Some of the synthesized compounds are endowed with antiproliferative activity against three human cancer cell lines. Their thermal reactivity suggests that the biological activity probably could not be linked to the Bergman cyclization.     

Bioactive compounds from brown seaweeds: Phloroglucinol,fucoxanthin and fucoidan as promising therapeutic agents against breast cancer

Breast cancer is one of the most common cancers among women and its incidence tends to increase year by year. Chemotherapy is an effective treatment for many types of cancer, however its toxicity in normal cells and acquired tumor resistance to the drug used are considered as the main barriers. New strategies have been proposed to increase the success of anticancer drugs namely it combination with natural dietary compounds, decreasing drug dose administered and reducing its toxicity to normal cells. Seaweeds are rich in bioactive compounds and, in Traditional Chinese Medicine and Japanese folk medicine are used to “treat” tumors. Attending to the attractive biological effects of some seaweed several efforts have been made to isolate the bioactive compounds and explore its action mechanisms. Phloroglucinol, fucoxanthin and fucoidan are bioactive compounds present in brown seaweed showing chemopreventive and chemotherapeutic effects against cancer. Several mechanisms namely antioxidant, cell cycle arrest, induction of cell death and inhibition of metastasis and angiogenesis have been mentioned as responsible for it anticancer activity. Beside the promising biological effects of these compounds, synergistic effects with cytotoxic drugs have been less explored. This review focuses on the potential protective and therapeutic effect – mainly against breast cancer – of the bioactive compounds phloroglucinol, fucoxanthin and fucoidan present in the brown seaweeds. Current knowledge about interaction between each of these compounds and the conventional anticancer drugs and the further research opportunities are discussed.     

Analogs of the marine alkaloid makaluvamines: synthesis, topoisomerase II inhibition, and anticancer activity

Twelve analogs of makaluvamines have been synthesized. These compounds were evaluated for their ability to inhibit the enzyme topoisomerase II. Five compounds were shown to inhibit topoisomerase catalytic activity comparable to two known topoisomerase II targeting control drugs, etoposide and m-AMSA. Their cytotoxicity against human colon cancer cell line HCT-116 and human breast cancer cell lines MCF-7 and MDA-MB-468 has been evaluated. Four makaluvamine analogs exhibited better IC(50) values against HCT-116 as compared to control drug etoposide. One analog exhibited better IC(50) value against HCT-116 as compared to m-AMSA. All 12 of the makaluvamine analogs exhibited better IC(50) values against MCF-7 and MDA-MB-468 as compared to etoposide as well as m-AMSA.     

Lichens: a promising source of antibiotic and anticancer drugs

Lichens are symbiotic associations between fungi and a photosynthetic alga and/or cyanobacteria. Lichenized fungi have been found to produce a wide array of secondary metabolites, most of which are unique to the lichenized condition. These secondary metabolites have shown an impressive range of biological activities including antibiotics, antifungal, anti-HIV, anticancer, anti-protozoan, etc. This review focuses primarily on the antibiotic and anticancer properties of lichen secondary chemicals. We have reviewed various publications related to antibiotic and anticancer drug therapies emphasizing results about specific lichens and/or lichen compounds, which microbes or cancer cells were involved and the main findings of each study. We found that crude lichen extracts and various isolated lichen compounds often demonstrate significant inhibitory activity against various pathogenic bacteria and cancer cell lines at very low concentrations. There were no studies examining the specific mechanism of action against pathogenic bacteria; however, we did find a limited number of studies where the mechanism of action against cancer cell lines had been explored. The molecular mechanism of cell death by lichen compounds includes cell cycle arrest, apoptosis, necrosis, and inhibition of angiogenesis. Although lichens are a reservoir for various biologically active compounds, only a limited number have been tested for their biological significance. There is clearly an urgent need for expanding research in this area of study, including in depth studies of those compounds which have shown promising results as well as a strong focus on identifying specific mechanisms of action and extensive clinical trials using the most promising lichen based drug therapies followed by large scale production of the best of those compounds.     

Synthesis and biological evaluation of 2-alkoxycarbonylallyl esters as potential anticancer agents

The reaction of carboxylic acids with Baylis-Hillman reaction derived α-bromomethyl acrylic esters readily provide 2-(alkoxycarbonyl)allyl esters in good to excellent yields. These functionalized allyl esters have been evaluated for their cell proliferation inhibition properties against breast cancer (MDA-MB-231 and 4T1) and pancreatic cancer (MIAPaCa-2) cell lines to explore their potential as anticancer agents. Several of the synthesized derivatives exhibit good potency against all three cancer cell lines. Our structure activity relationship (SAR) studies on 2-carboxycarbonyl allyl esters indicate that substituted aromatic carboxylic acids provide enhanced activity compared to substituted aliphatic carboxylic acid analogs. Di- and tri-allyl esters derived from di-and tri-carboxylic acids exhibit higher inhibition of cell proliferation than mono esters. Further SAR studies indicate that the double bond in the 2-(alkoxycarbonyl)allyl ester is required for its activity, and there is no increase in activity with increased chain length of the alkoxy group. Two lead candidate compounds have been identified from the cell proliferation inhibition studies and their preliminary mechanism of action as DNA damaging agents has been evaluated using epifluorescence and western blot analysis. One of the lead compounds has been further evaluated for its systemic toxicity in healthy CD-1 mice followed by anticancer efficacy in a triple negative breast cancer MDA-MB-231 xenograft model in NOD-SCID mice. These two in vivo studies indicate that the lead compound is well tolerated in healthy CD-1 mice and exhibits good tumor growth inhibition compared to breast cancer drug doxorubicin.     

Studies on the activity of three palladium(II) compounds of the form: trans-PdL2Cl2 where L=2-hydroxypyridine, 3-hydroxypyridine, and 4-hydroxypyridine

Three planaraminepalladium(II) complexes of the form: trans-PdCl(2)L(2), code named TH5, TH6 and TH7 where L=3-hydroxypyridine, 2-hydroxypyridine and 4-hydroxypyridine respectively have been investigated for antitumour activity against ovarian cancer cell lines: A2780, A2780(cisR) and A2780(ZD0473R). Although the compounds are generally found to be less active than cisplatin, they are often found to be more active against the resistant cell lines than the parent cell line. Among TH5, TH6 and TH7, TH6 which has two 2-hydroxypyridine non-labile ligands is found to be most active against the three cell lines. Variations in activity of TH5, TH6 and TH7 indicate that non-covalent interactions may be playing a significant role in activity. In particular, the results indicate that small changes in planaramine ligands such as the position of the polar OH group can have a more profound effect on activity of the compounds. Palladium compounds are generally found to be toxic rather tumour active because of much higher reactivity. Low but significant activity of trans-palladium(II) complexes TH5, TH6 and TH7 against the ovarian cancer cell lines indicates that it is believed to be associated with the decrease in their reactivity due to the presence of two sterically hindered planaramine ligands.     

Synthesis and biological evaluation of estradiol linked pyrrolo[2,1-c][1,4]benzodiazepine (PBD) conjugates as potential anticancer agents

A series of new estradiol linked pyrrolo[2,1-c][1,4]benzodiazepine (E(2)-PBD) conjugates (3a-f, 4a-f and 5a-f) with different linker architectures including a triazole moiety have been designed and synthesized. All the 18 compounds have been evaluated for their anticancer activity and it is observed that some of the compounds particularly 4c-e and 5c,d exhibited significant anticancer activity. The detailed biological aspects relating to the cell cycle effects and tubulin depolymerization activity have been examined with a view to understand the mechanism of action of these conjugates. Among all these conjugates, one of the compound 5c could be considered as the most effective compound particularly against MCF-7 breast cancer cell line.     

Degrasyn-like symmetrical compounds: Possible therapeutic agents for multiple myeloma (MM-I)

A series of degrasyn-like symmetrical compounds have been designed, synthesized, and screened against B cell malignancy (multiple myeloma, mantle cell lymphoma) cell lines. The lead compounds T5165804 and CP2005 showed higher nanomolar potency against these tumor cells in comparison to degrasyn and inhibited Usp9x activity in vitro and in intact cells. These observations suggest that this new class of compounds holds promise as cancer therapeutic agents.     

Anti-tumoral activity of imidazoquines,a new class of antimalarials derived from primaquine

The growth inhibitory activity of imidazoquines, antimalarial imidazolidin-4-ones derived from primaquine, on human cancer cell lines HT-29, Caco-2, and MCF-7 has been evaluated. Primaquine, N-dipeptidyl-primaquine derivatives, and other quinolines have been included in the study for comparison purposes. Primaquine and some of its derivatives were significantly active against the MCF-7 human breast cancer cell line, so these compounds might represent useful leads targeted at the development of novel specific agents against breast cancer. Conversely, all compounds were generally inactive against HT-29, with only one of the imidazoquines having IC₅₀ below 50 μM. Activities against the Caco-2 cell line were modest and did not follow any defined trend.     

Chemical composition and biological activity of triterpenes and steroids of chaga mushroom

Data on the chemical composition of triterpenic and steroid compounds, isolated from the chaga mushroom grown in natural environment or in a synthetic culture have been summarized. Special attention has been paid to the biological activity of chaga mushroom extracts and these particular compounds against various cancer cell lines in vitro and in vivo. This analysis has demonstrated some common features in inhibition of growth of various cell lines by chaga mushroom components. In this context, the most active are triterpene compounds containing OH group at C-22 and a side chain unsaturated bond.