Two new (1 and 2) and four known arylnaphthalene lignan lactones (3−6) were isolated from different plant parts of Phyllanthus poilanei collected in Vietnam, with two further known analogues (7 and 8) being prepared from phyllanthusmin C (4). The structures of the new compounds were determined by interpretation of their spectroscopic data and by chemical methods, and the structure of phyllanthusmin D (1) was confirmed by single-crystal X-ray diffraction analysis. Several of these arylnaphthalene lignan lactones were cytotoxic toward HT-29 human colon cancer cells, with compounds 1 and 7-O- [(2,3,4- (7) found to be the most potent, exhibiting IC 50 values of 170 and 110 nM, respectively. Compound 1 showed activity when tested in an in vivo hollow fiber assay using HT-29 cells implanted in immunodeficient NCr nu/nu mice. Mechanistic studies showed that this compound mediated its cytotoxic effects by inducing tumor cell apoptosis through activation of caspase-3, but it did not inhibit DNA topoisomerase IIα activity. C ancer is a serious threat to human health, and the discovery and development of promising new agents to treat this condition is therefore an urgent need. Natural products and their semisynthetic derivatives are used widely in cancer chemotherapy.1,2 As an example, etoposide (VP-16) is a semisynthetic aryltetralin lignan lactone glycoside modeled on the natural product podophyllotoxin. It targets DNA topoisomerase II (topo II) and has been utilized for decades to treat several types of cancer.3 However, side effects have been reported for etoposide, including myelosuppression and the development of secondary leukemias linked to topo II inhibitory activity. 4 Thus, it is highly desirable to discover new agents to treat cancer showing diverse mechanisms of action.Etoposide is a semisynthetic epipodophyllotoxin glycoside derived from podophyllotoxin that is a naturally occurring aryltetralin lignan lactone containing four stereogenic centers at its C-7, -8, -7′, and -8′ positions. Podophyllotoxin is well known to occur in Podophyllum peltatum and P. emodi var. hexandrum (syn. Sinopodophyllum hexandrum) (Berberidaceae). 3,5,6 The latter plant has been found to contain both aryltetralin and arylnaphthalene lignan lactones. 7 In a manner different from aryltetralin lignan lactones, arylnaphthalene lignan lactones are based on a naphthalene unit rather than a tetrahydronaph-

Eight new 16,23-epoxycucurbitacin derivatives, designated as elaeocarpucins A-H (1-8), and five known cucurbitacins (9-13) were isolated from the chloroform-soluble partitions of separate methanol extracts of the fruits and stem bark of Elaeocarpus chinensis collected in Vietnam. Isolation work was facilitated using a LC/MS dereplication procedure, and bioassay-guided fractionation was monitored using HT-29 human cancer cells. The structures of compounds 1-8 were determined on the basis of spectroscopic data interpretation, with the absolute configurations of isomers 1 and 2 established by the Mosher ester method. Compounds 1-13 were evaluated in vitro against the HT-29 cell line and using a mitochondrial transmembrane potential assay. Elaeocarpucin C (3), produced by partial synthesis from 16α,23α-epoxy-3β,20β-dihydroxy-10αH, 23βH-cucurbit-5,24-dien-11-one (13), was found to be inactive when evaluated in an in vivo hollow fiber assay using three different cancer cell types (dose range 0.5-10 mg/kg/day, ip).Elaeocarpus chinensis (Gardner & Champ.) Hook.f. ex Benth. (syn.: Friesia chinensis Gardner & Champ.), an evergreen tree of the family Elaeocarpaceae, is distributed mainly in subtropical or tropical areas of Asia, including southern mainland China, Laos, and Vietnam. 1 Besides being grown for ornamental purposes, E. chinensis is used also as a traditional Chinese herbal medicine for the treatment of emmeniopathy as well as * Corresponding Author, Tel: +1-614-247-8094. Fax: +1-614-247-8119. kinghorn@pharmacy.ohio-state.edu. # Dedicated to Dr. Gordon M. Cragg, formerly of the National Cancer Institute, Frederick, Maryland, for his pioneering work on the development of natural product anticancer agents.ASSOCIATED CONTENT Supporting Information. 1 H, 13 C and 2D NMR spectra of compounds 1-8, 1 H NMR of (R)-and (S)-MTPA esters of 1 and 2, and hollow fiber assay data for 3. This material is available free-of-charge via the Internet at http://pubs.acs.org. 28 and 16α,23α-epoxy-3β,20β-dihydroxy-10αH,23βH-cucurbit-5,24-dien-11-one (13). 11 Moreover, from the less potently cytotoxic CHCl 3 extract of the stem bark of the same plant, two additional new cucurbitacins, elaeocarpucins G (7) and H (8), were purified. Herein, we report the isolation and structure elucidation of the eight new compounds, 1-8, as well as the biological assessment of all isolates obtained in this investigation. -3β,20β-dihydroxy-10αH,23βH-cucurbit-5,24-dien-11-one (13), a known 16α,23α-epoxycucurbitane analogue first isolated from Eleaocarpus hainanensis 9 that was also identified in the present investigation. Comparison of the 1D-and 2D-NMR data of 1 with those of 13 revealed a major change evident in the side chain located at C-23, with a 2-methylprop-1-ene group in 13 being replaced by a 2-methylprop-2-en-1-ol moiety in 1. C-27) in the 13 C NMR spectrum. Moreover, key HMBC correlations from the terminal olefinic methylene protons of H-27 to C-24, C-25, and C-26, as well as H-24 and H-26 to C-27, supported the structure assigned ...

No abstract

CDB-4124 (Proellex or Telapristone acetate) is a modulator of progesterone receptor (PR) signaling which has been employed in preclinical studies for the treatment of uterine fibroids and endometriosis. Here we provide evidence for its action in breast cancer from both in vitro and in vivo studies. When CDB-4124 is given to rats at 200 mg/kg for 24 months it prevents the development of spontaneous mammary hyperplastic and premalignant lesions. In a second set of experiments, we found that CDB-4124, given as subcutaneous pellets at two different dose suppressed MNU-induced mammary carcinogenesis in rats in a dose dependent manner (see table below). The high dose (30 mg over 84 days) increased tumor latency from 66 to 87 days (P<0.02), decreased incidence from 85% to 35% (P<0.01), and multiplicity, from 3.0 to 1.1 tumors/animal (P<0.01). Tumor burden (total of all tumor weights in an animal) decreased from 2.6 g to 0.26 g/animal (P<0.01). Moreover in suport of our observations, CDB-4124 significantly suppressed Ki-67 positive cells from 30.5±7.1% in placebo-treated to 25.4±14.4% in low-dose and further to 10.3±4.5% (P<0.001) in the high-dose treated animals. CDB-4124 increased latency and inhibited the incidence, multiplicity and burden of mammary tumors CDB-4124 inhibited cell proliferation and induced apoptosis in these mammary tumors and this correlated with decreased proportion of PR+ tumor cells. Serum progesterone was lowered but there were no effects on estradiol. This progesterone receptor modulator appears to exert its effects in the presence of estrogen. In a mechanistic study employing human T47D breast cancer cells we found that CDB-4124 suppressed G1/0-S transition by inhibiting cdk-2 and cdk-4 expression and this correlated with inhibition of ER expression. Taken together, these data indicates that CDB-4124 can suppress the development of spontaneous and carcinogen-induced ER+ mammary tumors in rats and thus newer progesterone receptor modulators may have implications for prevention and treatment of human breast cancer. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-02-07.

No abstract