Ring A/B-Modified 17ß-Hydroxywithanolide Analogues as Antiproliferative Agents for Prostate Cancer and Potentiators of Immunotherapy for Renal Carcinoma and Melanoma.

Physachenolide C (1) is a 17ß-hydroxywithanolide natural product with a unique anticancer potential, as it exhibits potent and selective in vitro antiproliferative activity against prostate cancer (PC) cells and promotes TRAIL-induced apoptosis of renal carcinoma (RC) and poly I:C-induced apoptosis of melanoma cells. To explore the effect of ring A/B modifications of physachenolide C (1) on these biological activities, 23 of its natural and semisynthetic analogues were evaluated. Analogues 4-23 were prepared by chemical transformations of a readily accessible compound, physachenolide D (2). Compound 1 and its analogues 2-23 were evaluated for their antiproliferative activity against PC (LNCaP and 22Rv1), RC (ACHN), and melanoma (M14 and SK-MEL-28) cell lines and normal human foreskin fibroblast (HFF) cells. Most of the active analogues had selective and potent activity in reducing cell number for PC cell lines, some showing selectivity for androgen-independent and enzalutamide-resistant 22Rv1 cells compared to androgen-dependent LNCaP cells. Analogues with IC50s below 5.0 µM against ACHN cells, when tested in the presence of TRAIL, showed a significantly increased ability to reduce cell number, and those analogues active against the M14 and SK-MEL-28 cell lines exhibited enhanced activity when combined with poly I:C. These data provide additional structure-activity relationship information for 17ß-hydroxywithanolides and suggest that selective activities of some analogues may be exploited to develop natural products-based tumor-specific agents for cancer chemotherapy.

Strobiloscyphones A-F, 6-Isopentylsphaeropsidones and Other Metabolites from Strobiloscypha sp. AZ0266, a Leaf-Associated Fungus of Douglas Fir.

Six new 6-isopentylsphaeropsidones, strobiloscyphones A-F (1-6), and a new hexadecanoic acid, (2Z,4E,6E)-8,9-dihydroxy-10-oxohexadeca-2,4,6-trienoic acid (7), together with sphaeropsidone (8) and its known synthetic analogue 5-dehydrosphaeropsidone (9) were isolated from Strobiloscypha sp. AZ0266, a fungus inhabiting the leaf litter of Douglas fir (Pseudotsuga menziesii). The structures of 1-7 were established on the basis of their high-resolution mass and 1D and 2D NMR spectroscopic data, and their relative and/or absolute configurations were determined by NOE, comparison of experimental and calculated ECD spectra, and application of the modified Mosher's ester method. Of these, strobiloscyphone F (6) contains a novel highly oxygenated tetracyclic oxireno-octahydrodibenzofuran ring system. Natural products 1, 6, and 9 and the semisynthetic analogue 12 derived from 8 exhibited cytotoxic activity, whereas 9 and 12 showed antimicrobial activity. Possible biosynthetic pathways to 1-6, 8, and 9 are proposed.

An analog of withaferin A activates the MAPK and glutathione "stress" pathways and inhibits pancreatic cancer cell proliferation.

Withaferin A (WA) (1) and two analogs [4-epi-withaferin A (2) and 4,27-diacetyl-4-epi-withaferin A (3)] were evaluated for antitumor activity in pancreatic cancer cells. IC(50) for 1, 2, and 3 were 0.87, 0.45, and 0.29 ?M (BxPC-3); 1.28, 1.53, and 0.52 ?M (MIAPaCa-2); and 0.59, 2.25, and 0.56 ?M (PANC-1), respectively. We chose WA analog 3 for functional studies with confirmatory RT-PCR and Western blotting. ANOVA identified 33 (MIAPaCa-2), 54 (PANC-1), and 48 (BxPC-3) gene expression changes. Fisher exact test demonstrated MAPK and glutathione pathways to be overexpressed with WA analog 3. WA analog 3 elicits a dose- and time-dependent apoptosis, activates MAPK and glutathione ?stress? pathways, and inhibits proliferation.

Synthesis and preliminary biological evaluation of beta-carotene and retinoic acid oxidation products.

Synthesis of the beta-carotene oxidation product, 2,3-dihydro-5,8-endoperoxy-beta-apo-carotene-13-one (1) was achieved in six steps starting from beta-ionone. Photo-oxygenation of all trans-retinoic acid (8) and 13-cis-retinoic acid (9) produced a mixture of 5S*,8S*-epidioxy-5,8-dihydroretinoic acid (10) and 13-cis-5S*,8S*-epidioxy-5,8-dihydroretinoic acid (11). Methylation of the crude photo-oxygenation mixture afforded the corresponding methyl esters 12 and 13, respectively, both of which underwent ready aerial oxidation yielding hitherto unknown oxidation products of retinoic acid identified as methyl 5S*,8S*-epidioxy-9,10beta-epoxy-5,8,9,10-tetrahydroretinoate (14) and methyl 13-cis-5S*,8S*-epidioxy-9,10beta-epoxy-5,8,9,10-tetrahydroretinoate (15). Evaluation of 1, all trans-retinoic acid (8), 13-cis-retinoic acid (9), and the photo-oxygenation products 10-15 in a panel of five cancer cell lines showed 1 to be inactive and that 11 is significantly cytotoxic compared with the other retinoic acid analogs suggesting the requirement of the carboxylic acid moiety and the cis-geometry of the 13(14) double bond for cytotoxic activity.

Eupha-7,9(11),24-trien-3beta-ol ("antiquol C") and other triterpenes from Euphorbia antiquorum latex and their inhibitory effects on Epstein-Barr virus activation.

The structures of three triterpene alcohols isolated from the latex of Euphorbia antiquorum were established to be eupha-7,9(11),24-trien-3beta-ol (2; antiquol C), 19(10-->9)abeo-8alpha,9beta,10alpha-eupha-5,24-dien-3beta-ol (3; antiquol B), and 24-methyltirucalla-8,24(24(1))-dien-3beta-ol (4; euphorbol) on the basis of spectroscopic methods. Compounds 3 and 4 have previously been assigned the erroneous structures of 10alpha-cucurbita-5,24-dien-3alpha-ol and 24-methyleupha-8,24(24(1))-dien-3beta-ol, respectively. Compounds 2-4 and four other known compounds isolated from the latex, euphol (1), lemmaphylla-7,21-dien-3beta-ol (5), isohelianol (6), and camelliol C (7), showed potent inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA).