Ali El-Halawany

Resistance of solid tumors to treatment is significantly attributed to pharmacokinetic reasons at both cellular and multi-cellular levels. Anticancer agent must be bio-available at the site of action in a cytotoxic concentration to exert its proposed activity. P-glycoprotein (P-gp) is a member of the ATP-dependent membrane transport proteins; it is known to pump substrates out of cells in ATP-dependent mechanism. The over-expression of P-gp in tumor cells reduces the intracellular drug concentrations, which decreases the cytotoxicity of a broad spectrum of antitumor drugs. Accordingly, P-gp inhibitors/blockers are potential enhancer for the cellular bioavailability of several clinically important anticancer drugs such as, anthracyclines, taxanes, vinca alkaloids, and podophyllotoxins. Besides several chemically synthesized P-gp inhibitors/blockers, some naturally occurring compounds and plant extracts were reported for their modulation of multidrug resistance; however, this review will focus only on major classes of naturally occurring inhibitors viz., flavonoids, coumarins, terpenoids, alkaloids and saponins.

A Streptomyces strain MS-6-6 with promising anti-tuberculous activity was isolated from soil samples in Saudi Arabia. The nucleotide sequence of its 16S rRNA gene (1426 bp) evidenced a 100% similarity to Streptomyces mutabilis. Through an anti-tuberculous activity-guided approach, a polyketide macrolide was isolated and identified as treponemycin (TP). The structure of the isolated compound was determined by comprehensive analyses of its 1D and 2D NMR as well as HRESI-MS. In addition to the promising anti-tuberculous activity (MIC = 13.3 µg/mL), TP showed broad spectrum of activity against the Gram positive, Gram negative strains, and Candida albicans. Improvement of TP productivity (150%) was achieved through modification in liquid starch nitrate medium by replacing KNO3 with corn steep liquor and yeast extract or tryptone, and removing CaCO3 and K2HPO4. The follow up of TP percentage as well as its metabolites profile for each media was assessed by LC/DAD/MS.

Abstract Context: Mansonone G and mansorin A are major bioactive constituents from Mansonia gagei Drumm (Sterculiaceae) wood, and their mild anti-estrogenic activity was reported previously by the authors. Objective: In order to increase the potency of their anti-estrogenic effect and to clarify their binding way to estrogen receptor on a molecular level, several derivatives of both compounds will be prepared and a docking study of the original compounds and their derivatives on estrogen receptor alpha (ERα) was carried out. Materials and methods: The original compounds were isolated from the heartwood of M. gagei. Nine alkyl derivatives were prepared by acetylation, methylation, or adding a basic side chain to the free hydroxyl group of both compounds. The estrogenic/anti-estrogenic activities of the derivatives compared to the original compounds were carried out using ERα competitive binding screen and yeast two-hybrid assay expressing ERα and ERβ using concentrations ranging from 10 to 100 μM. Results: Acetyl mansonone G showed a 10-fold increase in its binding ability to ERα compared to mansonone G with an IC50 630 μM. Similarly, methyl mansonone G and acetyl mansonone G showed 50% and 35% inhibition of 17β-estradiol-induced β-galactosidase activity at 10 μM in the yeast expressing ERα, and 42% and 30%, respectively, at 10 μM in the yeast expressing ERβ. Virtual docking of acetyl mansonone G to ERα showed that it binds, with its acetyl oxygen, in a similar way to the 17β-OH of estradiol. Discussion and conclusion: The phenolic hydroxyl group in mansonones and mansorins was not essential for binding to estrogen receptors. In addition, acetyl mansonone G could represent a promising starting material for the synthesis of anti-estrogenic agents.

There is a growing demand for the discovery of new phytoestrogens to be used as a safe and effective hormonal replacement therapy.|The methanol extracts of 40 plants from the Egyptian and Thailand folk medicines were screened for their estrogen agonist and antagonist activities. The estrogenic and antiestrogenic effects of the tested extracts were carried out using the yeast two-hybrid assay system expressing ERα and ERβ. In addition, all the extracts were subjected to a naringinase treatment and retested for their estrogenic activity.|The methanol extracts of Derris reticulata and Dracaena lourieri showed the most potent estrogenic activity on both estrogen-receptor subtypes, while, the methanol extracts of Butea monosperma, Erythrina fusca, and Dalbergia candenatensis revealed significant estrogenic activity on ERβ only. Nigella sativa, Sophora japonica, Artabotrys harmandii, and Clitorea hanceana showed estrogenic effect only after naringinase treatment. The most potent antiestrogenic effect was revealed by Aframomum melegueta, Dalbergia candenatensis, Dracena loureiri, and Mansonia gagei.

There is a growing demand for the discovery of new phytoestrogens to be used as a safe and effective hormonal replacement therapy.|The methanol extracts of 40 plants from the Egyptian and Thailand folk medicines were screened for their estrogen agonist and antagonist activities. The estrogenic and antiestrogenic effects of the tested extracts were carried out using the yeast two-hybrid assay system expressing ERα and ERβ. In addition, all the extracts were subjected to a naringinase treatment and retested for their estrogenic activity.|The methanol extracts of Derris reticulata and Dracaena lourieri showed the most potent estrogenic activity on both estrogen-receptor subtypes, while, the methanol extracts of Butea monosperma, Erythrina fusca, and Dalbergia candenatensis revealed significant estrogenic activity on ERβ only. Nigella sativa, Sophora japonica, Artabotrys harmandii, and Clitorea hanceana showed estrogenic effect only after naringinase treatment. The most potent antiestrogenic effect was revealed by Aframomum melegueta, Dalbergia candenatensis, Dracena loureiri, and Mansonia gagei.