Semisynthetic analogues of the marine cembranoid sarcophine as prostate and breast cancer migration inhibitors

Sarcophine (1) is a bioactive cembranoid diterpene isolated from the Red Sea soft coral Sarcophyton glaucum. Previous semisynthesis attempts resulted in decreased or complete loss of 1's anticancer activity. Sarcophine and analogues showed antimigratory activity against breast and prostate cancer cell lines. This encouraged further semisynthestic optimizations to improve its activity and establish a preliminary structure-activity relationship. Eight new and five known semisynthetic analogues were generated. These compounds were evaluated for their ability to inhibit growth, proliferation, and migration of the prostate and breast metastatic cancer cell lines PC-3 and MDA-MB-231, respectively. Most analogues exhibited enhanced antimigratory activity.     

Synthesis of chalcone derivatives on steroidal framework and their anticancer activities

Chalcone derivatives on estradiol framework have been synthesized. Some of the derivatives showed potent anticancer activity against some human cancer cell lines. Compounds 9 and 19 showed potent activity against MCF-7, a hormone dependent breast cancer cell line. Chalcone 7 was further modified to the corresponding indanone derivative (19) using the Nazarov reaction, which showed better activity than the parent compound against the MCF-7 breast cancer cell line. Active anticancer derivatives were also evaluated for osmotic hemolysis using the erythrocyte as a model system. It was observed that chalcone derivatives showing cytotoxicity against cancer cell lines did not affect the fragility of erythrocytes and hence may be considered as non-toxic to normal cells.     

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 of D- and L-tyrosine-chlorambucil analogs active against breast cancer cell lines

A series of D- and L-tyrosine-chlorambucil analogs was synthesized as anticancer drugs for chemotherapy of breast cancer. The novel compounds were synthesized in good yields through efficient modifications of D- and L-tyrosine. The newly synthesized compounds were evaluated for their anticancer efficacy in different hormone-dependent and hormone-independent (ER+ and ER-) breast cancer cell lines. The novel analogs showed significant in vitro anticancer activity when compared to chlorambucil. Structure-activity relationship (SAR) reveals both, the influence of the length of the spacer chain and the stereochemistry of the tyrosine moiety. Interestingly, the D- and L-tyrosinol-chlorambucil derivatives with 10 carbon atoms spacer are selective towards MCF-7 (ER+) breast cancer cell line.     

Synthesis and anticancer activity of 2-benzylidene indanones through inhibiting tubulin polymerization

In an attempt to discover a potent and selective anticancer agent, gallic acid has been modified to benzylidene indanones as tubulin polymerization inhibitors. These compounds were evaluated against several human cancer cell lines and also evaluated for inhibition of tubulin polymerase in in vitro assays. Three of the analogues exhibited strong cytotoxicity against human cancer cell lines IC(50)=10-880 nM and also showed tubulin polymerization inhibition (IC(50)=0.62-2.04 μM). Compound 9j, the best candidate of the series was found to be non-toxic in acute oral toxicity in Swiss-albino mice up to 1000 mg/kg dose.     

Synthesis and in vitro anticancer and antitubercular activity of diarylpyrazole ligated dihydropyrimidines possessing lipophilic carbamoyl group

A series of dihydropyrimidine derivatives were synthesized by utilizing Biginelli reaction and evaluated for their in vitro anticancer activity against MCF-7 human breast cancer (HBC) cell line using sulforhodamine B (SRB) assay and antitubercular activity against Mycobacterium tuberculosis (MTB) H(37)Rv using Microplate Alamar Blue Assay (MABA). Compounds 13p, 13t were exhibited 70.6% and 63.7% of HBC cell growth inhibition at 10 μM concentration. Interestingly compound 13p was also found to be the most potent in the series against MTB H(37)Rv with MIC value of 0.125 μg/mL.     

Photochemical synthesis and anticancer activity of barbituric acid,thiobarbituric acid,thiosemicarbazide, and isoniazid linked to 2-phenyl indole derivatives

2-Phenyl-1H-indole-3-carbaldehyde-based barbituric acid, thiobarbituric acid, thiosemicarbazide, isoniazid, and malononitrile derivatives were synthesized under photochemical conditions. The antitumor activities of the synthesized compounds were evaluated on three different human cancer cell lines representing prostate cancer cell line DU145, Dwivedi (DWD) cancer cell lines, and breast cancer cell line MCF7. All the screened compounds possessed moderate anticancer activity, and out of all the screened compounds, 5-{1[2-(4-chloro-phenyl)2-oxo-ethyl]-2-phenyl-1H-indole-3-ylmethylene}-2-thioxo-dihydro-pyrimidine-4,6-dione (2b) and 5-{1[2-(4-methoxy-phenyl)2-oxo-ethyl]-2-phenyl-1H-indole-3-ylmethylene}-2-thioxo-dihydro-pyrimidine-4,6-dione (2d) exhibited marked antitumor activity against used cell lines. Additionally, barbituric acid derivatives were selective to inhibit cell line DWD and breast cancer cell lines.     

Synthesis,Cytotoxicity and Antimicrobial Evaluation of New Coumarin‐Tagged β‐Lactam Triazole Hybrid

A series of coumarin‐tagged β‐lactam triazole hybrids ( 10a – 10o ) were synthesized and tested for their cytotoxic activity against MDA‐MB‐231 (triple negative breast cancer), MCF‐7 (estrogen receptor positive breast cancer (ER+)) and A549 (human lung carcinoma) cancer cell lines including one normal cell line, HEK‐293 (human embryonic kidney). Two compounds 10b and 10d exhibited substantial cytotoxic effect against MCF‐7 cancer cell lines with IC₅₀ values of 53.55 and 58.62 μm , respectively. More importantly, compounds 10b and 10d were non‐cytotoxic against HEK‐293 cell lines. Structure–activity relationship (SAR) studies suggested that the nitro and chloro group at the C‐3 position of phenyl ring are favorable for anticancer activity, particularly against MCF‐7 cell lines. Furthermore, antimicrobial evaluation of these compounds revealed modest inhibition of examined pathogenic strains with compounds 10c and 10i being the most promising antimicrobial agents against Pseudomonas aeruginosa and Candida albicans, respectively.     

Design, synthesis, and biological evaluation of N-acetyl-S-(p-chlorophenylcarbamoyl)cysteine and its analogs as a novel class of anticancer agents

N-Acetyl-S-(p-chlorophenylcarbamoyl)cysteine (NACC) was identified as a metabolite of sulofenur. Sulofenur was demonstrated to have broad activity against solid tumors in preclinical studies but exhibited disappointing clinical responses due to its high protein binding related adverse effects. NACC exhibited low protein binding and excellent activity against a sulofenur sensitive human colon cancer cell line. In this study, analogs of NACC were synthesized and evaluated with four human cancer cell lines. Two of the NACC analogs showed excellent activity against two human melanoma cell lines, while NACC remains the most potent of the series. All three compounds were more potent than dacarbazine, which is used extensively in treating melanoma. NACC was shown to induce apoptosis without affecting the cell cycle. Further, NACC exhibited low toxicity against monkey kidney cells. The selective anticancer activity, low toxicity, an unknown yet but unique anticancer mechanism and ready obtainability through synthesis make NACC and its analogs promising anticancer agents.     

Molecular designing and in silico evaluation of darunavir derivatives as anticancer agents

Darunavir is a synthetic nonpeptidic protease inhibitor which has been tested for anticancer properties. To deduce and enhance the anticancer activity of the Darunavir, we have modified its reactive moiety in an effective way. We designed 9 analogues in ChemBioOffice 2010 and minimized using the LigPrep tool of Schrödinger 2011. These analogues can obstruct the activity of other signalling pathways which are implicated in many tumors. Results of the QikProp showed that all the analogues lied in the specified range of all the pharmacokinetic (ADMET) properties required to become the successful drug. Docking study was performed to test its anticancer activity against the biomarkers of the five main types of cancers i.e. bone, brain, breast, colon and skin cancer. Grid was generated for each oncoproteins by specifying the active site amino acids. The binding model of best scoring analogue with each protein was assessed from their G-scores and disclosed by docking analysis using the XP visualizer tool. An analysis of the receptor-ligand interaction studies revealed that these nine Darunavir analogues are active against all cancer biomarkers and have the features to prove themselves as anticancer drugs, further to be synthesized and tested against the cell lines.     

Synthesis and preliminary evaluation of curcumin analogues as cytotoxic agents

A series of curcumin analogues with different substituents at the 4-position of the phenyl group were synthesized and screened for in vitro cytotoxicity against a panel of human cancer cell lines. Several novel curcumin analogues, especially 32 and 34, exhibited selective and potent cytotoxic activity against human epidermoid carcinoma cell line A-431 and human glioblastoma cell line U-251, implying their specific potential in the chemoprevention and chemotherapy of skin cancer and glioma. The preliminary SAR information extracted from the results suggested that introduction of appropriate substituents to the 4′-positions could be a promising approach for the development of new cytotoxic curcumin analogues with special selectivity for A-431 and U-251 cell lines.     

Synthesis of some quinazolinones inspired from the natural alkaloid L-norephedrine as EGFR inhibitors and radiosensitizers

A set of quinazolinones synthesized by the aid of L-norephedrine was assembled to generate novel analogues as potential anticancer and radiosensitizing agents. The new compounds were evaluated for their cytotoxic activity against MDA-MB-231, MCF-7, HepG-2, HCT-116 cancer cell lines and EGFR inhibitory activity. The most active compounds 5 and 6 were screened against MCF-10A normal cell line and displayed lower toxic effects. They proved their relative safety with high selectivity towards MDA-MB-231 breast cancer cell line. Measurement of the radiosensitizing activity for 5 and 6 revealed that they could sensitize the tumour cells after being exposed to a single dose of 8 Gy gamma radiation. Compound 5 was able to induce apoptosis and arrest the cell cycle at the G2-M phase. Molecular docking of 5 and 6 in the active site of EGFR was performed to gain insight into the binding interactions with the key amino acids.     

Synthesis and evaluation of novel sulfonamide analogues of 6/7-aminoflavones as anticancer agents via topoisomerase II inhibition

A series of new sulfonamide analogues of 6/7-aminoflavones were synthesized by using molecular hybridization approach. These new sulfonamide analogues were screened for antiproliferative activity against human hepatocellular carcinoma (HepG-2), human lung cancer cell line (A-549), human colorectal adenocarcinoma (Caco-2) cancer cell lines. Compounds 5p, 5q, 5t, 5v, 5w and 5x exhibited good anticancer activity against selected cancer cell lines. These compounds were further evaluated to predict their ability to inhibit topoisomerase-II enzyme. Compound 5x has shown potent antiproliferative activity (IC₅₀ value 0.98 µM) as compared to standard drug Adriamycin (IC₅₀ = 0.94 µM) indicating that these compounds exhibits anticancer activity via inhibition of topoisomerase-II enzyme. Docking results also have supported above observations by indicating that compounds are held in the active pocket by combination of various hydrogen and hydrophobic interactions with Top II-DNA-etoposide enzyme.     

Semisynthesis and in vitro anticancer activities of andrographolide analogues

The plant Andrographis paniculata found throughout Southeast Asia contains Andrographolide 1, a diterpenoid lactone, which has antitumour activities against in vitro and in vivo breast cancer models. In the present study, we report on the synthesis of andrographolide derivatives, 3,19-isopropylideneandrographolide (2), 14-acetyl-3,19-isopropylideneandrographolide (3) and 14-acetylandrographolide (4), and their in vitro antitumour activities against a 2-cell line panel consisting of MCF-7 (breast cancer cell line) and HCT-116 (colon cancer cell line). Compounds 2 and 4 were also screened at the US National Cancer Institute (NCI) for their activities against a panel of 60 human cancer cell lines derived from nine cancer types. Compound 2 was found to be selective towards leukaemia and colon cancer cells, and compound 4 was selective towards leukaemia, ovarian and renal cancer cells at all the dose-response parameters. Compounds 2 and 4 showed non-specific phase of the cell cycle arrest in MCF-7 cells treated at different intervals with different concentrations. NCI's COMPARE and SOM mechanistic analyses indicated that the anticancer activities of these new class of compounds were not similar to that of standard anticancer agents, suggesting novel mechanism(s) of action.     

Design,synthesis, and in silico study of hybrid oxoazetidine conjugated thiazoles as anti-EGFR with cytotoxicity activity

We report a series of hybrid oxoazetidine conjugated thiazoles as epidermal growth factor receptor (EGFR) inhibitors, which were synthesized and tested using a variety of in silico and in vitro studies. The compounds were found to be active against breast and hepatic cancer cell lines, with Compounds 7a, 7b , and 7e being the most potent ones. The derivatives were also evaluated for molecular docking and complementarity studies to explicate fundamental substituent groups essential for their bioactivity. Moreover, the structural activity relationship of the analogues was performed for future compound optimization. These studies advocated that the analogues have a high affinity towards EGFR with favorable anticancer potential. The study advised that the derivatives have potency against breast and hepatic cancer and can assist as an initial scaffold for further development of anti-EGFR compounds.     

Thalidomide analogues demonstrate dual inhibition of both angiogenesis and prostate cancer

The identification of agents with antiproliferative activity against endothelial cells has significant value for the treatment of many angiogenesis-dependent pathologies. Herein, we describe the discovery of a series of thalidomide analogues possessing inhibitory effects against both endothelial and prostate cancer cells. More specifically, several analogues exhibited low micromolar to mid-nanomolar potency in the inhibition of human microvascular endothelial cell (HMEC) proliferation, both in the presence and absence of vascular endothelial growth factor (VEGF), with the tetrafluorophthalimido class of compounds demonstrating the greatest potency. Additionally, all the compounds were screened against two different androgen independent prostate cancer cell lines (PC-3 and DU-145). Again, the tetrafluorophthalimido analogues exhibited the greatest effect with GI(50) values in the low micromolar range. Thalidomide was found to demonstrate selective inhibition of androgen receptor positive LNCaP prostate cancer cells. Furthermore, we showed that, as an example, tetrafluorophthalimido analogue 19 was able to completely inhibit the prostate specific antigen (PSA) secretion by the LNCaP cell line, while thalidomide demonstrated a 70% inhibition. We have also demonstrated that a correlation exists between HMEC and prostate cancer cell proliferation for this structural class. Altogether, our study suggests that these analogues may serve as promising leads for the development of agents that target both androgen dependent and independent prostate cancer and blood vessel growth.     

Design,Synthesis and Anticancer Evaluation of New Substituted Thiophene-Quinoline Derivatives

A series of new isoxazolyl, triazolyl and phenyl based 3-thiophen-2-yl-quinoline derivatives were synthesized adopting click chemistry approach. In addition, the synthesis of new useful synthon, (2-chloroquinolin-3-yl) (thiophen-2-yl) methanol, is reported. The obtained compounds were characterized by spectral data analysis and evaluated for their anticancer activity. All the derivatives were subjected to in vitro MTT cytotoxicity screening assay against a panel of four different human cancer cell lines, liver (HepG-2), colon (HCT-116), human cervical cancer (HeLa) and breast (MCF-7). Out of a library of 17 compounds, two compounds have been identified as potent and selective cytotoxic agents against HeLa and MCF-7 cell lines. SAR studies for such hybridized analogues were investigated and phenyl derivatives were proved to be more potent than isoxazole and triazole derivatives. Furthermore, the promising compounds were selected for in vitro inhibition of EGFR-TK and Topo II enzymes. Also, they were subjected to cell cycle arrest analysis and apoptosis assay on MCF-7 cells. Our recent finding highlights these thiophene-quinoline analogues as a promising class of compounds for further studies concerning new anticancer therapies.     

Newer human inosine 5′-monophosphate dehydrogenase 2 (hIMPDH2) inhibitors as potential anticancer agents

Human inosine 5′-monophosphate dehydrogenase 2 (hIMPDH2), being an age-old target, has attracted attention recently for anticancer drug development. Mycophenolic acid (MPA), a well-known immunosuppressant drug, was used a lead structure to design and develop modestly potent and selective analogues. The steep structure–activity relationship (SAR) requirements of the lead molecule left little scope to synthesise newer analogues. Here, newer MPA amides were designed, synthesised and evaluated for hIMPDH2 inhibition and cellular efficacy in breast, prostate and glioblastoma cell lines. Few title compounds exhibited cellular activity profile better than MPA itself. The observed differences in the overall biological profile could be attributed to improved structural and physicochemical properties of the analogues over MPA. This is the first report of the activity of MPA derivatives in glioblastoma, the most aggressive brain cancer.     

A laccase-catalysed one-pot synthesis of aminonaphthoquinones and their anticancer activity

Nuclear monoamination of a 1,4-naphthohydroquinone with primary aromatic amines was catalysed by the commercial laccase, Novozym 51003, from Novozymes to afford aminonaphthoquinones. The synthesis was accomplished by reacting a mixture of the primary amine and 1,4-naphthohydroquinone in succinate-lactate buffer and a co-solvent, dimethylformamide, under mild reaction conditions in a vessel open to air at pH 4.5 and pH 6.0. Anticancer screening showed that the aminonaphthoquinones exhibited potent cytostatic effects particularly against the UACC62 (melanoma) cancer cell line (GI(50)=3.98-7.54 μM). One compound exhibited potent cytostatic effects against both the TK10 (renal) and the UACC62 (melanoma) cancer cell line. The cytostatic effects of this compound (GI(50)=8.38 μM) against the TK10 cell line was almost as good as that of the anticancer agent, etoposide (GI(50)=7.19μM). Two compounds exhibited potent cytostatic effects against both the UACC62 (melanoma) and the MCF7 (breast) cancer cell lines. The total growth inhibition (TGI) of most of the compounds was better than that of etoposide against the UACC62 cell line. Three compounds (TGI=7.17-7.94 μM) exhibited potent cytostatic effects against the UACC62 cell line which was 7 to 8-fold better than that of etoposide (TGI=52.71 μM). The results are encouraging for further study of the aminonaphthoquinones for potential application in anticancer therapy.     

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.