Jennifer K Schilling’s research while affiliated with Virginia Tech and other places

Bioassay-guided fractionation of a methanol extract of the fruits of Eucalyptus camaldulensis Dehnh. with moderate antiproliferative activity afforded the new triterpene, 3β-acetoxy-urs-11,13(18)-dien-28-oic acid (1) along with the known triterpenoids 3β-hydroxy-urs-11-en-28,13β-olide (2), 3β-acetoxy-urs-11-en-28,13β-olide (3), 3-acetylbetulinic acid (4), oleanolic acid (5), ursolic acid (6), β-amyrin acetate (7), β-sitosterol (8) and sitosterol 3-O-β-D-glucopyranoside (9). Their structures were established on the basis of analysis of their 1H and 13C NMR, APT, gHSQC, gHMBC, UV, IR and mass spectral data. The tested triterpenoids (1–7) exhibited weak-moderate antiproliferative activity against the A2780 human ovarian cancer cell line.

The composition of the water-distilled essential oils of the berries and leaves of Juniperus excelsa. M. Bieb. were analyzed by gas chromatography-mass spectrometry (GC-MS). The main components in the berries of J. excelsa., accounting for 56.1% of the oil, were determined as α-pinene (34.0%), cedrol (12.3%), L-verbenol (5.4%), and D-verbenol (4.4%) while in the leaves of J. excelsa., accounting for 63.2% of the oil, were found to be α-pinen (29.7%), cedrol (25.3%), α-muurolene (4.4%), and 3-carene (3.8%). Cytotoxic and antimicrobial potential of the berries and leaves of J. excelsa. were investigated.

Salvia hypargeia. Fisch. et Mey. (Lamiaceae) root extract, among 16 Salvia. extracts, showed the highest activity against the human ovarian cancer cell line. Bioactivity-guided fractionation of this plant extract has yielded four abietane-type diterpenes [5,6-didehydro-7-hydroxytaxodone (1), 14-deoxycoleon U (= 6-hydroxysalvinolone) (2), demethylcryptojaponol (3), and salvicanaric acid (4)] two triterpenes (lupeol and lupeol-3-acetate), and a fatty acid mixture consisting mainly of palmitic acid (51.6%) and palmitoleic acid (6.4%). Compounds 2 and 3 were found to be active against A2780 human ovarian cancer cell line with IC50 values of 3.9 and 1.2 μ g/mL, respectively, and the fatty acid composition was the most active part of the extract (IC50 = 0.6 μ g/mL).

Four new N-(arylsufanyl)carbonyl paclitaxel analogues (2a-d) were prepared from 7-(triethylsilyl)-protected baccatin III (5). Their cytotoxicities against human ovarian (A2780) and prostate cancer (PC3) cell lines, as well as their tubulin-assembly activities, were determined. In these assays, the new compounds showed rather weak activities, one two orders of magnitude below those of paclitaxel (taxol; 1). The known 3'-N-[(thiophen-2-yl)carbonyl] paclitaxel analogue 3 was also prepared. As previously reported, 3 exhibited strongly improved cytotoxicities and tubulin-assembly activities as compared to paclitaxel (1).

Bioassay-guided fractionation of the MeOH and EtOAc fractions of extracts of two lianas collected in Suriname has led to the isolation of five new diterpenoids, humirianthone 1, 1-hydroxy-humirianthone 2, 15R-humirianthol 3, patagonol 4, and patagonal 5, and the five known diterpenoids, humirianthol 7, annonalide 8, acrenol 9, icacinol 10, and the oxidized annonalide 11. All 10 diterpenoids showed cytotoxic activity against the A2780 human ovarian cancer cell line, and compounds 1, 3, 8, and 9 also showed activity against phytopathogenic fungi.

Ten taxoids with a cyclopropanated side chain were synthesized by coupling a spirocyclopropanated oxazoline-5-carboxylic acid with 7-(triethylsilyl)baccatin III, followed by hydrolytic ring opening and benzoyl migration. The absolute configuration of the 2′-position was determined by NMR analysis of the corresponding Mosher esters. These paclitaxel analogs were active in A2780 mammalian and PC-3 prostate cancer cell lines, and also in a tubulin-assembly assay, but all the analogs were less active than paclitaxel itself. To probe the basis for the uniform potency reduction shown by the cyclopropanated taxoid series, we have examined the conformational properties of compound 3b alone by molecular mechanics and in complex with tubulin by molecular dynamics. In addition, we have performed an NMR/NAMFIS conformer deconvolution analysis for compound 3b. Both modeling and NAMFIS approaches provide a satisfying understanding of the biological behavior of the series of cyclopropanated taxoids and provide further, though indirect, support for the T-form as characteristic of taxoids bound to β-tubulin. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

Bioassay-guided fractionation of an EtOAc extract of the leaves of Melampodium camphoratum using an assay for inhibitors of the degradation of hemin resulted in the isolation of six new eudesmane sesquiterpenes (1-6) and the known 6-epi-beta-verbesinol coumarate (7). The structures of compounds 1-6 were established as 6alpha-(4'-O-methyl-7'E-coumaryloxy)eudesm-4(14)-ene (1), 6alpha-({4'-O-stearyl}-7'E-coumaryloxy)eudesm-4(14)-ene (2), 6alpha-({4'-O-palmityl}-7'E-coumaryloxy)eudesm-4(14)-ene (3), 6alpha-({4'-O-[9' 'Z-hexadecenoyl]}-7'E-coumaryloxy)eudesm-4(14)-ene (4), 6alpha-(7'Z-coumaryloxy)eudesm-4(14)-ene (5), and 6alpha-({4'-acetoxy}-7'Z-coumaryloxy)eudesm-4(14)-ene (6). Compounds 1-4 showed weak activity in the hemin degradation assay, while compounds 5-7 were inactive.

Five macrocyclic paclitaxel bis-lactones and their corresponding open chain taxoids were synthesized as models of the tubulin-binding conformation of paclitaxel. Macrocyclic lactones with a 19-21-membered ring underwent isomerization to form smaller rings. The lactones were evaluated for cytotoxicity and tubulin-polymerization ability. All five macrocyclic paclitaxel lactones were active, but less so than paclitaxel, while the rearranged macrocyclic lactones and the corresponding open-chain taxoids were much less active or inactive.