Anti-diabetic activities of phenolic compounds of Alternaria sp., an endophyte isolated from the leaves of desert plants growing in Egypt.

Six phenolic compounds (talaroflavone (1), alternarienoic acid (2), altenuene (3), altenusin (4), alternariol (5), and alternariol-5-O-methyl ether (6)) were isolated from the solid rice culture media of Alternaria sp., an endophyte isolated from the fresh leaves of three desert plants, Lycium schweinfurthii Dammer (Solanaceae), Pancratium maritimum L. (Amaryllidaceae) and Cynanchum acutum L. (Apocynaceae). Compounds 2, 3, and 4 exhibited potent α-glucosidase and lipase inhibitory activities suggesting that they might act as naturally occurring anti-diabetic candidates. The same compounds showed potent binding in the active site for both enzymes with desirable pharmacokinetic properties. The isolated bioactive compounds were not exclusive to a certain host plant which reveals the dominant ecological standpoints for consequent optimization. This could lead to a cost-effective and reproducible yield applicable to commercial scale-up.

Lycium schweinfurthii: new secondary metabolites and their cytotoxic activities.

Two new compounds, 11S-methoxy-11,12-dihydro phytuberin (2) and 9S-methoxy-benzocyclononan-7-one (6), together with twenty-six known ones were isolated from Lycium schweinfurthii (Solanaceae). Their planar structure was established by extensive spectroscopic analyses. The absolute configuration of compound 6 was determined by time dependent density functional theory calculations (TDDFT). The cytotoxic potential of the isolates was assessed in cultured skin cancer (G-361) and colon cancer (HCT-116 and CaCo-2) cell lines. Certain flavonoids showed the highest cytotoxic activity, with IC50 values ranging from 7.1 to 63.3 µM; meanwhile 5-flurouracil showed IC50 values ranging from 62.4 to >100 µM. All compounds showed minimal toxicity towards normal cells from skin (NHDF-4) and colon (CCD-841), indicating their potential selectivity and safety as cytotoxic candidates.

A new glucoside with a potent α-glucosidase inhibitory activity from Lycium schweinfurthii.

A new glucoside, 3-methoxy-4-O-ß-D-glucopyranosyl-methyl benzoate, has been isolated from Lycium schweinfurthii along with five known compounds through bioactivity guided fractionation of the total plant methanolic extract towards α-glucosidase inhibitory activity. All the isolated compounds were tested for their inhibitory effect on α-glucosidase enzyme. As a result, four of them showed a potent inhibitory activity and thus constitute a therapeutic approach to decrease postprandial hyperglycemia in diabetic patients.

Design and pharmacophore modeling of biaryl methyl eugenol analogs as breast cancer invasion inhibitors.

Cell invasion and migration are required for the parent solid tumor cells to metastasize to distant organs. Microtubules form a polarized network, enabling organelle and protein movement throughout the cell. Cytoskeletal elements coordinately regulate cell's motility, adhesion, migration, exocytosis, endocytosis, and division. Thus, microtubule disruption can be a useful target to control cancer cell invasion and metastasis. The phenolic ether methyl eugenol (1), the major component of the essential oil of the leaves of Melaleuca ericifolia Sm. (Myrtaceae), was used as a starting scaffold to design eleven new and three known anti-tubulin agents 2-15 using carbon-carbon coupling reactions. A computer-assisted approach was used to design these new biaryl derivatives using colchicine-binding site of tubulin as the molecular target and colchicine as an active ligand. Several derivatives showed potent inhibitory activity against MDA-MB-231 cell migration at the 1-4microM dose range. The Z isomers, 4 and 15 were more active as invasion inhibitors compared to their structurally related E isomers, 2 and 14. The cytotoxic activities of compounds 2-15 against two breast cancer cell lines MDA-MB-231 and MCF-7 were evaluated. Anti-invasive activity of the semisynthetic derivatives is not due to a direct cytotoxic effect on MDA-MB-231. Analogs 2-15 may promote their anti-invasive activity through the induction of changes in cell morphology. A pharmacophore model was generated involving seven essential features for activity, which was consistent with a previously generated colchicine site inhibitors model.

Rational design and semisynthesis of betulinic acid analogues as potent topoisomerase inhibitors.

Chemical transformation studies were conducted on betulinic acid (1), a common plant-derived lupane-type triterpene. Eleven new rationally designed derivatives of 1 (2-5 and 7-13) were synthesized based on docking studies and tested for their topoisomerase I and IIalpha inhibitory activity. Semisynthetic reactions targeted C-3, C-20, and C-28 in 1. Structures of the new compounds were confirmed by spectroscopic methods (1D and 2D NMR and MS). Compound 9, 3-O-[N-(phenylsulfonyl)carbamoyl-17beta-N-(phenylsulfonyl)amide]betulinic acid, showed 1.5-fold the activity of CPT in a topoisomerase I DNA relaxation assay. Four out of 14 betulinic acid analogues (5, 9, 11, and 12) showed 1.5-fold the activity of etoposide in a topoisomerase II assay. The new analogues exhibited better cytotoxic activities against the human colon cancer cells SW948 and HCT-116 and the breast cancer cell line MDA-MB-231 compared to the parent (1). Betulinic acid (1) is a potential scaffold for the design of new topoisomerase I and IIalpha inhibitors.

Antiproliferative triterpenes from Melaleuca ericifolia.

Three new 28-norlupane triterpenes, 28-norlup-20(29)-en-3beta-hydroxy-17beta-hydroperoxide (1), 28-norlup-20(29)-en-3beta-hydroxy-17alpha-hydroperoxide (2), and 20 S-17beta,29-epoxy-28-norlupan-3beta-ol (3), were isolated from the leaves of Melaleuca ericifolia along with eight known pentacyclic triterpenes. The structures of the new compounds were elucidated by spectroscopic methods including 1D and 2D NMR spectroscopy and mass spectrometry. The isolated triterpenes were evaluated for antiproliferative activity against the malignant +SA mammary epithelial cell line.