Biological Evaluation Committee Research Articles

Design and synthesis of new series of dipyrromethane-coumarin and porphyrin-coumarin derivatives: Excellent anticancer agents

Coumarin analogues of dipyrromethane and porphyrin derivatives were synthesized and tested for their in-vitro anticancer activity at NCI (USA). Seven of the obtained compounds, 4-(di(1H-pyrrol-2-yl)methyl)-6-methoxy-2H-chromen-2-one (2c), 4-((1H-pyrrol-2-yl)(2H-pyrrol-2-ylidene)methyl)-6-methyl-2H-chromen-2-one (3a), 4-((1H-pyrrol-2-yl)(2H-pyrrol-2-ylidene)methyl)-6-chloro-2H-chromen-2-one (3d), Tetrahydro(6-methyl-coumarin) calix [4]pyrroles (4a), Tetrahydro(6-methoxy-coumarin) calix [4]pyrroles (4c), Tetra(6-methyl-coumarin) calix [4]pyrroles (5a) and Tetra(6-methoxy-coumarin) calix [4]pyrroles (5c) were screened for their antiproliferative activity against 60 human cancer cell lines. Among seven selected compounds, 2c, 3a, 4a and 4c showed remarkable activity with GI50 values around 1. 0 μM (54 out of 60 cell lines) and <1. 0 μM (59 out of 60 cell lines) respectively. Interestingly, two compounds 2c and 4a have been subjected more than three times for repeat analysis against all the 60 cell lines and have been referred to Biological Evaluation Committee (BEC) for their advance study, among these two, compound 2c has been referred to BEC three times. Further, the ct-DNA interaction, absorptions and fluorescence quenching results of more active compounds 2c and 4a are quite promising.

Synthesis, in vitro and in vivo biological evaluation of substituted 3-(5-imidazo[2,1-b]thiazolylmethylene)-2-indolinones as new potent anticancer agents

A small library of 3-(5-imidazo[2,1-b]thiazolylmethylene)-2-indolinones has been synthesized and screened according to protocols available at the National Cancer Institute (NCI). Some derivatives were potent antiproliferative agents, showing GI50 values in the nanomolar range. Remarkably, when most active compounds against leukemia cells were tested in human peripheral blood lymphocytes from healthy donors, were 100–200 times less cytotoxic. Some compounds, selected by the Biological Evaluation Committee of NCI, were examined to determine tubulin assembly inhibition. Furthermore, flow cytometric studies performed on HeLa, HT-29, and A549 cells, showed that compounds 14 and 25 caused a block in the G2/M phase. Interestingly, these derivatives induced apoptosis through the mitochondrial death pathway, causing in parallel significant activation of both caspase-3 and -9, PARP cleavage and down-regulation of the anti-apoptotic proteins Bcl-2 and Mcl-1. Finally, compound 25 was also tested in vivo in the murine BL6-B16 melanoma and E0771 breast cancer cells, causing in both cases a significant reduction in tumor volume.

Design, synthesis and docking study of pyridine and thieno[2,3-b] pyridine derivatives as anticancer PIM-1 kinase inhibitors

A series of pyridine and thieno[2,3-b]pyridine derivatives have been designed and synthesized as anticancer PIM-1 kinase inhibitors. Thirty-seven compounds were selected by NCI to be tested initially at a single dose (10 µM) in the full NCI 60 cell line panel. Compound 5b showed potent anticancer activity and was tested twice in the five-dose assay which confirmed its potent antitumor activity (GI50 values 0.302–3.57 µM) against all tested tumor cell lines except six cell lines where they showed moderate sensitivity. This compound was sent to NCI biological evaluation committee and still under consideration for further testing. In addition, the most active anticancer compounds in each series, 5b, 8d, 10c, 13h, and 15e, were evaluated for their PIM-1 kinase inhibitory activity. Compound 8d was the most potent one with IC50 = 0.019 µM followed by 5b, 15e, 10c and 13h with IC50 values 0.044, 0.083, 0.128 and 0.479 µM respectively. Moreover, docking study of the most active compounds in PIM-1 kinase active site was consistent with the in vitro activity.

Synthesis, antiproliferative and anti-inflammatory activities of some novel 6-aryl-2-(p-(methanesulfonyl)phenyl)-4,5-dihydropyridazi-3(2H)-ones

Sixteen new 6-aryl-2-(p-(methanesulfonyl)phenyl)-4,5-dihydropyridazi-3(2H)-ones (2a–p) were synthesized and tested for in vitro anticancer and in vivo anti-inflammatory activities. Eleven (2b, 2d, 2e–j and 2m–p) of the obtained compounds were screened for their antiproliferative activity towards 60 human cancer cell lines by the National Cancer Institute (USA). Compound 2f showed remarkable activity with GI50 less than 1 μM on 36 human tumor cell lines and has been referred to Biological Evaluation Committee (NCI) for advance study. Compound 2g also displayed promising antiproliferative activity against 20 different cell lines with GI50 less than 1 μM. Compounds 2k and 2n were found to have a comparable anti-inflammatory activity to that of standard drug etoricoxib in carrageenan-induced rat hind paw edema model at 5 h.

Synthesis of novel quinoline-2-one based chalcones of potential anti-tumor activity

Novel quinoline-2-one based chalcones were synthesized from a Claisen–Schmidt condensation by using the couple KOH/1,4-dioxane as reaction medium. A relatively stable aldol was isolated and identified as the intermediate species in the formation of the target chalcones. Nine of the obtained compounds were in vitro screened by the US National Cancer Institute (NCI) for their ability to inhibit 60 different human tumor cell lines. Products 16c, 16d, 16h and 27 exhibited the highest activity, being compound 27 the most active, displaying remarkable activity against 50 human tumor cell lines, thirteen of them with GI50 values ≤1.0 μM, being the HCT-116 (Colon, GI50 = 0.131 μM) and LOX IMVI (Melanoma, GI50 = 0.134 μM) the most sensitive strains. Compound 27 was referred to in vivo acute toxicity and hollow fiber assay by the Biological Evaluation Committee of the NCI. The acute toxicity study indicated that compound 27 was well tolerated intraperitoneally (150 mg/kg/dose) by athymic nude mice. This compound may possibly be used as lead compound for developing new anticancer agents.

Synthesis and evaluation of anticancer activity of some novel 6-aryl-2-(p-sulfamylphenyl)-pyridazin-3(2H)-ones

A series of novel pyridazinone derivatives bearing benzenesulfonamide moiety (2a-h) has been synthesized by the condensation of appropriate aroylacrylic acid and 4-hydrazinobenzenesulfonamide hydrochloride in ethanol. Five derivatives (2a, 2b, 2d, 2g and 2h) were evaluated for their anticancer activity toward human cancer cell lines by the National Cancer Institute. The 2h showed remarkable activity against SR (leukemia) and NCI-H522 (non-small cell lung) with a GI(50) value of less than 0.1 μM. It also displayed good activity against leukemia (CCRF-CEM, HL-60 (TB), K-562, MOLT-4, RPMI-8226), non-small cell lung cancer (NCI-H460), colon (HCT-116, HCT-15, HT29, KMI2, SW-620), CNS (SF-295), melanoma (MALME-3M, M14, MDA-MB-435 SK-MEL-5), ovarian (OVCAR-3, NCI/ADR-RES) and breast (MCF7) cancer cell lines with a GI(50) less than 1.0 μM. The acute toxicity study of 2h indicated that it is well tolerated intra-peritoneally (400 mg/kg) by athymic nude mice. The 2h may possibly be used as lead compound for developing new anticancer agents.

Synthesis and Cytotoxic Studies of Hydroximino Derivatives of Some 16E-Arylidenosteroids

Oxime and dioxime derivatives of various 16E-arylidenosteroids in the androstene series have been prepared and evaluated at the National Cancer Institute (NCI), Bethesda (USA) for their antineoplastic activity against various tumor cell lines in order to determine the structural requirements for cytotoxic activity. Aldol condensation of dehydroepiandrosterone (DHA) and DHA acetate with various aldehydes followed by treatment with hydroxylamine hydrochloride resulted in the formation of 16E-arylidenosteroid-oxime system. Oximes 15, 16 and compound 20 with a higher degree of oxidation in ring A have been found active in a 60 cell line antitumor prescreen by virtue of their cytotoxic effect against one or more tumor cell line and were further referred for in vivo hollow fiber bioassay. These compounds showed interesting intraperitoneal and subcutaneous scores in the in vivo hollow fiber bioassay and have been referred to the Biological Evaluation Committee for Cancer Drugs for further detailed in vivo testing.

Biostructural Features of Additional Jasplakinolide (Jaspamide) Analogues

The cyclodepsipeptide jasplakinolide (1) (aka jaspamide), isolated previously from the marine sponge Jaspis splendens, is a unique cytotoxin and molecular probe that operates through stabilization of filamentous actin (F-actin). We have recently disclosed that two analogues of 1, jasplakinolides B (3) and E, were referred to the National Cancer Institute's (NCI) Biological Evaluation Committee, and the objective of this study was to reinvestigate a Fijian collection of J. splendens in an effort to find jasplakinolide congeners with similar biological properties. The current efforts have afforded six known jasplakinolide analogues (4-7, 9, 10), two structures requiring revision (8 and 14), and four new congeners of 1 (11-13, 15) including open-chain derivatives and structures with modified β-tyrosine residues. Compounds were evaluated for biological activity in the NCI's 60 cell line screen and in a microfilament disruption assay in both HCT-116 and HeLa cells. These two phenotypic screens provide evidence that each cytotoxic analogue, including jasplakinolide B (3), operates by modification of microfilaments. The new structure jasplakinolide V (13) has also been selected for study by the NCI's Biological Evaluation Committee. In addition, the results of a clonogenic dose-response study on jasplakinolide are presented.

Synthesis and evaluation of anticancer activity of 2-arylamino-6-trifluoromethyl-3-(hydrazonocarbonyl)pyridines

The synthesis and anticancer activity of 2-arylamino-6-trifluoromethyl-3-(hydrazonocarbonyl)pyridines is described. The new trifluoromethylpyridine derivatives were evaluated for their anticancer activity toward human cancer cell lines by the National Cancer Institute (NCI). Most of them had excellent growth inhibition activity, having GI 50 values in the low micromolar to nanomolar concentration range. The most potent 2,6-dichlorobenzaldehydehydrazone 29 inhibited the growth of all tested cancer cell lines with nanomolar potency, and did not show animal toxicity. Hydrazone 29 has been selected by the Biological Evaluation Committee of NCI for testing in vivo Hollow Fiber Assay.

Synthesis and evaluation of antitumoral activity of ester and amide derivatives of 2-arylamino-6-trifluoromethyl-3-pyridinecarboxylic acids

The synthesis and antitumoral activity of ester and amide derivatives of 2-arylamino-6-trifluoromethyl-3-pyridinecarboxylic acids 8– 58 is described. Trifluoromethylpyridine derivatives 8– 58 were evaluated for their anticancer activity toward human tumoral cell lines by the National Cancer Institute (NCI). Most of them possess encouraging anticancer activity, having GI 50 values in the low micromolar to nanomolar concentration range. The 3,4,5-trimethoxyphenylamide 44 was the most active, and it is now under review by NCI Biological Evaluation Committee for possible further studies.

Antitumor Activity of Substituted E-3-(3,4,5-Trimethoxybenzylidene)-1,3-dihydroindol-2-ones

The design and synthesis of anticancer E-3-(3,4,5-trimethoxybenzylidene)-1,3-dihydroindol-2-ones is reported. Strong COMPARE correlations among the cell line responses suggest that these compounds may be acting similarly through a combination of different mechanisms of action. The 5-methoxy derivative (2h) was the most active compound with a mean pGI50 of 6.34, and it is now under review by Biological Evaluation Committee of the National Cancer Institute for possible further studies.

Synthesis and Antitumor Activity of New Thiosemicarbazones of 2‐Acetylimidazo[4,5‐b]pyridine.

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Synthesis and antitumor activity of new thiosemicarbazones of 2-acetylimidazo[4,5-b]pyridine

A number of thiosemicarbazones of 2-acetyl-imidazo[4,5-b]pyridine were prepared in order to investigate their in vitro antineoplastic activities. Three compounds: (i) 2-acetylimidazo[4,5-b]pyridin-4-sec-butyl-3-thiosemicarbazone [(A7), NSC674098], (ii) 2-acetylimidazo[4,5-b]pyridin-4-tert-butyl-3-thiosemi-carbazone [(A9), NSC674099], (iii) 2-acetylimidazo[4,5-b]pyridin-4-cyclohexyl-3-thiosemicarbozone [(A11), NSC674101] showed remarkable activity against some of the cell lines tested. The Biological Evaluation Committee of N.C.I. determined that further secondary testing should be carried out (these compounds were tested against prostate cancer).

Antitumor Activity of New Substituted 3-(5-Imidazo[2,1-b]thiazolylmethylene)-2-indolinones and Study of Their Effect on the Cell Cycle

This paper reports the synthesis of a new series of 3-(5-imidazo[2,1-b]thiazolylmethylene)-2-indolinones which were tested as potential antitumor agents at the National Cancer Institute. Two derivatives are now under review by BEC (Biological Evaluation Committee of NCI). To investigate the mechanism of action, the effect on cell cycle progression was studied by monitoring them in colon adenocarcinoma HT-29: both were able to block HT-29 in mitosis. 3-[(2,6-Dimethylimidazo[2,1-b]thiazol-5-yl)methylene]-5-chloro-2-indolinone was the most active compound.

Synthesis and Cytotoxic Studies of Hydroximino Derivatives of Some 16E‐Arylidenosteroids.

Oxime and dioxime derivatives of various 16E-arylidenosteroids in the androstene series have been prepared and evaluated at the National Cancer Institute (NCI), Bethesda (USA) for their antineoplastic activity against various tumor cell lines in order to determine the structural requirements for cytotoxic activity. Aldol condensation of dehydroepiandrosterone (DHA) and DHA acetate with various aldehydes followed by treatment with hydroxylamine hydrochloride resulted in the formation of 16E-arylidenosteroid-oxime system. Oximes 15, 16 and compound 20 with a higher degree of oxidation in ring A have been found active in a 60 cell line antitumor prescreen by virtue of their cytotoxic effect against one or more tumor cell line and were further referred for in vivo hollow fiber bioassay. These compounds showed interesting intraperitoneal and subcutaneous scores in the in vivo hollow fiber bioassay and have been referred to the Biological Evaluation Committee for Cancer Drugs for further detailed in vivo testing.

Substituted E-3-(2-Chloro-3-indolylmethylene)1,3-dihydroindol-2-ones with antitumor activity

The synthesis and antitumor activity of a new series of E-3-(2-chloro-3-indolylmethylene)1,3-dihydroindol-2-ones is described. Several compounds were active on the primary test (three human cell lines) and entered the second level (60 human cell lines). All of them were potent growth inhibitors with GI50 ranging from −5.32 to −7.27. Four are now under review by BEC (Biological Evaluation Committee of the NCI). The most potent antitumor derivatives were also evaluated as cardiotonic agents (in view of a possible coanthracyclinic activity). In order to find a possible mechanism of action their effects on cell cycle progression in an adenocarcinoma cell line (HT29) were tested, evidencing that these molecules are able to block HT29 in mitosis. The introduction of new substituents in the indolinone moiety while maintaining the same chloroindole portion generated interesting derivatives. 3-(2-Chloro-5-methoxy-6-methyl-3-indolylmethylene)5-hydroxy-1,3-dihydroindol-2-one was the most active of the whole series. It was more potent than vincristine against seven of the nine tumors considered. Moreover it was selective towards some cell lines such as MDA-MB-435 (breast), OVCAR-3 (ovarian) and SK-MEL-28 (melanoma). Even the introduction of a benzyl ring at the nitrogen of the chloroindole portion, gave rise to potent compounds.

Synthesis and antineoplastic activity of 2-alkylaminoethyl derivatives of various steroidal oximes

Various steroidal oxime ether derivatives in androstene and estrane series have been synthesized and evaluated for the antineoplastic activity at National Cancer Institute, Bethesda, Maryland, USA. O-Alkylation of the oximes by various alkylaminoethyl halides gave the oxime ether derivatives. The 17α-ethynylandrostene derivatives 29 (DPJ-684), 30 (DPJ-685), 31 (DPJ-686) and estrane derivatives 35 (DPJ-531) and 36 (DPJ-532) were among the small percentage of compounds, which have been screened by NCI for in vivo hollow fiber assay by virtue of their activity against one or more human tumour cell lines in 60 cell line in vitro prescreen. The preliminary in vivo reports of hollow fiber assays have been referred to the Biological Evaluation Committee for Cancer Drugs for considering these compounds for further detailed in vivo testing.