Structure activity relationships of antiproliferative rocaglamide derivatives from Aglaia species (Meliaceae)

Eleven rocaglamide derivatives (cyclopentatetrahydrobenzofurans) and one structurally related aglain congener all isolated from different Aglaia species (Meliaceae) were tested for growth inhibiting properties using the human cancer cell lines MONO-MAC-6 and MEL-JUSO. Proliferation of both cell lines was efficiently inhibited in a dose and compound dependent manner. Applying MTT-Assay, the IC50 of the most active compound didesmethyl-rocaglamide (1) was observed at 0.002 and 0.006 micrograms/ml (0.004 and 0.013 microM) depending on the cell line investigated. Bulky aminoacyl substituents at C-2, acetylation of the OH substituent at C-1 or insertion of a OH or OMe substituent at C-3 of the rocaglamide skeleton all diminished the activity of the compounds investigated. The aglain derivative 12 was inactive up to a concentration of 3 micrograms/ml (4.6 microM). This loss of activity is assumed to be mainly due to the presence of a pyran ring in the aglains vs. a furan ring as found in rocaglamide derivatives. Rocaglamide derivatives may act primarily by inhibition of cell proliferation as evidenced by the absence of a significant cytotoxic effect in long-term cultures of MONO-MAC-6 cells treated with high doses of didesmethylrocaglamide. Our data suggest that rocaglamide derivatives could exert a potential role in the treatment of malignant diseases and are worth to be investigated in further studies of experimental medicine and pharmacology.     

Ponapensin, a cyclopenta[bc]benzopyran with potent NF-kappaB inhibitory activity from Aglaia ponapensis

Two new compounds, a cyclopenta[bc]benzopyran, ponapensin (1), and an aglaialactone, 5,6-desmethylenedioxy-5-methoxy-aglalactone (2), together with nine known compounds were isolated from the CHCl(3) soluble extract of the leaves and twigs of Aglaia ponapensis. Their structures were established by spectroscopic data interpretation. Ponapensin (1) exhibited significant NF-kappaB inhibitory activity in an Elisa assay, and was found to be more potent than the positive control rocaglamide. All of the compounds isolated were also tested in a panel of human cancer cell lines, with the known sterol E-volkendousin (3) and methyl rocaglate (aglafoline) found to be the only active substances.     

Two new rocaglamide derivatives from twigs of Aglaia odorata var. microphyllina

Phytochemical investigation of Aglaia odorata var. microphyllina led to the isolation of two new rocaglamide derivatives and three known ones. The structures of the two new compounds were elucidated as 8b-methoxy-desmethylrocaglamide (1) and 3′-hydroxy-8b-methoxy-rocaglamide (2) by spectroscopic techniques (IR, MS, 1D and 2D NMR) and comparing with published data. All the five compounds were evaluated for cytotoxic activity against K562 cell line by MTT method. The results indicated that the OH at 8b position was a decisive group for cytotoxic activity.     

Insecticidal flavaglines and other compounds from Fijian Aglaia species

Bioassays with lipophilic crude extracts of four Fijian Aglaia species against Spodoptera littoralis displayed strong insecticidal activity for A. basiphylla and A. gracilis, whereas A. archboldiana and A. vitiensis did not have any significant effects. The insect toxicity of A. basiphylla was caused by the well known benzofuran flavaglines rocaglamide, desmethylrocaglamide and aglafoline. In contrast, A. gracilis contained four related pyrimidinone derivatives in the root and stem bark, including two new congeners named marikarin and 3'-hydroxymarikarin. Moreover, two new putrescine bisamides, secoodorine and secopiriferine, a new benzopyran flavagline. desacetylaglain A. and a new norsesquiterpene were isolated from the leaves together with three known bisamides and 3-hydroxy-5,7,4'-trimethoxyflavone. The structures of the new compounds were elucidated by spectroscopic methods. Comparative feeding assays within the active pyrimidinone flavaglines showed that the free hydroxy group in aromatic ring A of marikarin diminishes insecticidal activity.     

Insecticidal rocaglamide derivatives from Aglaia spectabilis (Meliaceae)

Bark of Aglaia spectabilis collected on the island of Phu Quoc (Vietnam) yielded insecticidal cyclopentatetrahydrobenzofurans of the rocaglamide type including four new natural products. Structure elucidation of the new compounds is described. All rocaglamide derivatives isolated exhibited strong insecticidal activity towards neonate larvae of the polyphagous pest insect Spodoptera littoralis when incorporated into an artificial diet. LC50 values varied from 0.8 to 80 ppm. The most active compounds isolated, methylrocaglate and C-3' hydroxylmethylrocaglate, were similar with regard to their insecticidal activity to the well-known natural insecticide azadirachtin.     

Triterpenoids,lignans and a benzofuran derivative from the bark of Aglaia elaeagnoidea

One 1H-cyclopentatetrahydro[b]benzofuran, two lignans, two dammarane triterpenoids and one limonoid were isolated from the bark of Aglaia elaeagnoidea. The structures of the isolated compounds were established on the basis of spectral data. The lignan trans-2,3-bis(3,4,5-trimethoxybenzyl)-1,4-butanediol diacetate and 20S,24S-epoxy-25-hydroxymethyldammarane-3-one are new compounds. trans-3,4-Bis(3,4,5-trimethoxybenzyl)tetrahydrofuran has been synthesized, but not previously reported as a natural product.     

Discovery and structure-activity relationship of N-phenyl-1H-pyrazolo[3,4-b]quinolin-4-amines as a new series of potent apoptosis inducers

We report the discovery and SAR study of a series of N-phenyl-1H-pyrazolo[3,4-b]quinolin-4-amines as potent inducers of apoptosis. N-(3-Acetylphenyl)-2,3-dihydro-1H-cyclopenta[b]quinolin-9-amine (2) was discovered through our cell- and caspase-based HTS assays as an inducer of apoptosis. Compound 2 is active against cancer cells derived from several human solid tumors, with EC(50) values ranging from 400 to 700 nM. SAR study of hit 2 led to the discovery of N-phenyl-1H-pyrazolo[3,4-b]quinolin-4-amines as a novel series of potent apoptosis inducers, with 1,3-dimethyl-N-(4-propionylphenyl)-1H-pyrazolo[3,4-b]quinolin-amine (6b) having EC(50) values ranging from 30 to 70 nM in cancer cells. These compounds also demonstrated potent activity in the cell growth inhibition assay, with GI(50) values of 16-42 nM for compound 6b.     

Importance of the central region of lamprey gonadotropin-releasing hormone III in the inhibition of breast cancer cell growth

Naturally occurring isoforms of the decapeptide gonadotropin-releasing hormone (GnRH) share residues 1-4 and 9-10. lGnRH-III, the third isoform isolated in the sea lamprey has no endocrine effect in mammals but shows a direct antiproliferative effect on human breast, prostate and endometrial cancer cell lines. To investigate these features, residues 5-8 of lGnRH-III were systematically replaced with Ala. The ability of the synthetic analogs to interact with receptors on MDA-MB 231 human breast cancer cells and their effect on the growth of the same cell line were investigated. [Ala6]lGnRH-III and [Ala7]lGnRH-III have neither receptor binding nor antiproliferative activity. Replacement of His5 with Ala resulted in an analog that binds to the receptor but does not have antiproliferative activity. The results are in agreement with previous reports that modifications of Lys at position 8 are well tolerated.     

Synthesis of New Aromatic Pyrrolo[2,1- c] [1,4]benzodiazepines and Pyrrolo[1,2- a] thieno[3,2- e] [1,4]diazepines as Anti-tumoral Agents

Diazepine analogs of thieno[2,3- b] pyrrolizin-8-ones were synthesized by aromatization of 2-hydroxypyrrolo[1,2- a] thieno[3,2- e] [1,4]diazepines. These compounds were evaluated in vitro for their antiproliferative activity against the L1210 leukemia cell line. The activity of these compounds was in the micromolar range, the best result being for the mixture of the isomers 5 and 6 which showed a 0.35 μM IC 50 against cell growth.     

Phenolic constituents from the core of kenaf (Hibiscus cannabinus)

Four lignans, boehmenan H [2-(4-hydroxy-3-methoxyphenyl)-5-[3-(4-hydroxy-3-methoxycinnamoyloxy)propyl]-3-hydroxymethyl-7-methoxybenzodihydrofuran], boehmenan K [2-(4-hydroxy-3-methoxyphenyl)-5-[3-(4-hydroxycinnamoyloxy)-1-propenyl]-3-(4-hydroxy-3-methoxycinnamoyloxymethyl)-7-methoxybenzodihydrofuran], threo-carolignan H [threo-1-(4-hydroxy-3-methoxyphenyl)-2-[4-[3-(4-hydroxy-3-methoxycinnamoyloxy)propyl]-2-methoxyphenoxy]-1,3-propanodiol], and threo-carolignan K [threo-1-(4-hydroxy-3-methoxyphenyl)-3-(4-hydroxy-3-methoxycinnamoyloxy)-2-[4-[3-(4-hydroxycinnamoyloxy)-1-propenyl]-2-methoxyphenoxy]-1-propanol] as well as several other lignans, aldehydes and a tyramine derivative were isolated from the acetone extract of core of kenaf (Hibiscus cannabinus). All the structures were established by spectroscopic methods. The hitherto unreported 13C NMR spectra of some compounds are also presented and discussed. 2D NMR techniques have allowed the revision of certain previously reported 13C NMR assignments of some scarce naturally occurring compounds.     

Structure-activity relationship of conformationally constrained peptidomimetics for antiproliferative activity in HER2-overexpressing breast cancer cell lines

Human epidermal growth factor receptor 2 (HER2) is a member of the human epidermal growth factor receptor kinases and is involved in a signaling cascade for cell growth and differentiation. It is well established that HER2-mediated heterodimerization has important implications in cancer. Deregulation of signaling pathways and overexpression of HER2 is known to occur in cancer cells, indicating the role of HER2 in tumorigenesis. Therefore, blocking HER2-mediated signaling has potential therapeutic value. We have designed several peptidomimetics to inhibit HER2-mediated signaling for cell growth. One of the compounds (compound 5, Arg-[3-amino-3(1-napthyl)-propionic acid]-Phe) exhibited antiproliferative activity with IC(50) values in the nanomolar to micromolar range in breast cancer cell lines. To further investigate the structure-activity relationship of the compounds, various analogs of compound 5 were designed. Conformational constraints were initiated in the peptidomimetic with introduction of a Pro residue in the peptidomimetic sequence. Results of antiproliferative activity indicated that analogs of compound 5 with C-and N-terminal ends capped (compound 16) and compound 9 with Asp at the C-terminal exhibited antiproliferative activity in the lower micromolar range against breast cancer cell lines. Introduction of conformational constraints such as Pro residue in the sequence or cyclization did not enhance the activity of the peptidomimetic. Competitive binding studies were carried out to evaluate the binding of potent peptidomimetics to HER2-overexpressing cancer cell lines. Results indicated that compounds exhibiting antiproliferative activity in breast cancer cell lines bind to the cells that overexpress HER2 protein.     

Activity-guided isolation of cytotoxic constituents from the bark of Aglaia crassinervia collected in Indonesia

Activity-guided fractionation of a CHCl(3)-soluble partition of the MeOH extract of the bark of Aglaia crassinervia collected in Indonesia led to the isolation of three new glabretal-type triterpenoids, aglaiaglabretols A-C (1-3), as well as nine known compounds, 3-epi-cabraleahydroxylactone (4), cabraleahydroxylactone (5), rocaglaol (6), 2beta,3beta-dihydroxy-5alpha-pregn-17(20)-(E)-16-one, scopoletin, and mixtures of cabraleadiol and epicotillol and of beta-sitosterol and stigmasterol. The structures of compounds 1-3 were determined on the basis of spectroscopic and chemical methods. The structure of aglaiaglabretol A (1) was confirmed by single-crystal X-ray analysis, and the absolute stereochemistry of this isolate was established by the Mosher ester method. The cytotoxic activity of all isolates and several chemical transformation products obtained in the present study was evaluated. The known cyclopenta[b]benzofuran, rocaglaol (6), was found to be significantly active and comparable in potency to the positive controls, paclitaxel and camptothecin. Aglaiaglabretol B (2) was further tested in an in vivo hollow fiber model.     

Design, synthesis, and biological evaluation of substituted 2,3-dihydro-1H-cyclopenta[b]quinolin-9-ylamine related compounds as fructose-1,6-bisphosphatase inhibitors

In a search for structurally new inhibitors of fructose-1,6-bisphosphatase (F16BPase), substituted 2,3-dihydro-1H-cyclopenta[b]quinoline derivatives were synthesized. It has been shown that the 2,3-dihydro-1H-cyclopenta[b]quinoline moiety may represent a suitable scaffold for the synthesis of potent F16BPase inhibitors endowed with significantly lower EGFR tyrosine kinase inhibitory activity.     

Novel,potent and selective cyclin D1/CDK4 inhibitors: indolo[6,7-a]pyrrolo[3,4-c]carbazoles

The synthesis and CDK inhibitory properties of a series of indolo[6,7-a]pyrrolo[3,4-c]carbazoles is reported. In addition to their potent CDK activity, the compounds display antiproliferative activity against two human cancer cell lines. These inhibitors also effect strong G1 arrest in these cell lines and inhibit Rb phosphorylation at Ser780 consistent with inhibition of cyclin D1/CDK4.     

Effects of antiandrogens on growth of androgen-dependent mouse mammary tumor (Shionogi carcinoma 115) in vivo and in vitro

Binding affinities of modified steroidal anthrasteroids, 3 beta-hydroxy-3a beta,6-dimethyl-2,3,3a,4,5,8,9,10,10a beta,11,11a beta, 11b alpha-dodecahydro-1H-cyclopenta[a]anthracene-8-one (1) and 3a beta,6-dimethyl-2,3,3a,4,5,8,9,10,10a beta,11,11a beta,11b alpha-dodecahydro-1H-cyclopenta[a]anthracene-3,8-dione (2), the steroid oxendolone and the nonsteroid AA560, for the androgen receptor (AR) of Shionogi carcinoma 115 (SC115) and their effects on the growth of SC115 were investigated in vivo and in vitro. The inhibitory effects of these compounds on testosterone 5 alpha-reductase of SC115 tissues were also measured. The relative binding affinities of these compounds were 3.17-0.03% of that of dihydrotestosterone, and their rank order was (1) greater than AA560 greater than oxendolone much greater than (2). In the presence of 10(-9) M testosterone, anthrasteroids and AA560 inhibited the growth of SC115 cells at 10(-7) M in a serum-free medium, but oxendolone did not. In the absence of testosterone, (1), (2) and oxendolone promoted cell growth at 10(-6), 10(-7) and 10(-7) M, respectively. However, AA560 nearly completely blocked cell growth at 10(-5) M. At a 2 mg daily dose for 13 days, (1) and AA560 powerfully inhibited tumor growth in castrated DS mice treated with testosterone propionate but oxendolone had almost no effect. Anthrasteroids and oxendolone showed weak but significant agonistic activity in vivo. Anthrasteroids markedly inhibited 5 alpha-reductase activity of SC115, oxendolone weakly and AA560 not at all. The remarkable antiandrogenic activities of (1) and AA560 may partially result from their higher affinities for the AR of SC115 but other yet unknown mechanisms may also contribute to these activities.     

Antifungal and anthelmintic activity of novel benzofuran derivatives containing thiazolo benzimidazole nucleus: an in vitro evaluation

A novel series of thiazolo[3,2-a]benzimidazole derivatives containing benzofuran nucleus (5a–l) have been synthesized. The key intermediate, substituted benzimidazol-sulfanyl benzofuran ethanone (3a–d) was prepared by refluxing the mixture of substituted 2-acetyl benzofuran and substituted 2-mercaptobenzimidazole in acetic acid. The cyclisation of compounds (3a–d) using polyphosphoric acid furnished the corresponding 6-substituted benzofuran thiazolo[3,2-a]benzimidazoles (4a–d). Further, the cyclized compounds (4a–d) were subjected for Mannich reaction to give corresponding Mannich bases (5a–l). All newly synthesized compounds were screened for antifungal and anthelmintic activity. Amongst the tested compounds, 4b and 4d exhibited potential antifungal activity. From the anthelmintic activity data, it was found that the compounds 3a, 3b and 5i were found to be more effective against the tested earthworm Pheretima posthuma. In correlation to anthelmintic activity, the selected compounds were subjected for molecular docking studies and the compounds 3a and 5i have emerged as active anthelmintic agents with maximum binding affinity (?3.7 and ?5.4 kcal/mol).     

Modulation of cell proliferation in rat liver cell cultures by new calix[4]arenes

Cell cycle progression is dependent on intracellular iron level and chelators lead to iron depletion and decrease cell proliferation. This antiproliferative effect can be inhibited by exogenous iron. In this work, we present the synthesis of new synthetic calix[4]arene podands bearing two aspartic/glutamic acid, ornithine groups or hydrazide function at the lower rim, designed as potential iron chelators. The synthesis only afforded calix[4]arenes in the cone conformation. We report their effect on cell proliferation, in comparison with the new oral chelator ICL670A (4-[3,5-bis-(2-hydroxyphenyl)-1,2,4-triazol-1-yl]-benzoic acid). The antiproliferative effect of these new compounds was studied in the rat hepatoma cell line Fao by measuring mitochondrial succinate dehydrogenase activity. Their cytotoxicity was evaluated by extracellular LDH activity. Preliminary results indicated that among all tested compounds, monohydrazidocalix[4]arene 2 which is not cytotoxic in Fao cells exhibits interesting antiproliferative activity. This effect, independent on iron depletion, remains to be further explored. Moreover, it also shows that new substituted calix[4]arenes could open the way to new valuable medicinal chemistry scaffolding.     

Matrix compare analysis discriminates subtle structural differences in a family of novel antiproliferative agents, diaryl-3-hydroxy-2,3,3a,10a-tetrahydrobenzo[b]cycylopenta[e]azepine-4,10(1H,5H)-diones

A diastereoselective synthesis of diaryl-3-hydroxy-2,3,3a,10a-tetrahydrobenzo[b]cycylopenta[e]azepine-4,10(1H,5H)-diones is described employing a tandem Michael-aldol addition as key step. The novel compounds exhibit antiproliferative activity in a panel of in vitro cultivated cancer cell lines. The bioinformatic tool COMPARE was able to discriminate between two closely related subgroups of the title compounds, namely 1,3- and 2,3-disubstituted derivatives.