Antiproliferative Compounds from Cleistanthus boivinianus from the Madagascar Dry Forest

The two new lignans 3a-O-(b-D-glucopyranosyl)- desoxypodophyllotoxin (1) and 4-O-(b-D-glucopyranosyl)-dehydropodophyllotoxin (2) were isolated from Cleistanthus boivinianus, together with the known lignans deoxypicropodophyllotoxin (3), (±)-b-apopicropodophyllin (4), (-)- desoxypodophyllotoxin (5), (-)-yatein (6), and b-peltatin-5-O-b-D-glucopyranoside (7). The structures of all compounds were characterized by spectroscopic techniques. Compounds 1, 4, and 5 showed potent antiproliferative activities against the A2780 ovarian cancer cell line, with IC₅₀ values of 33.0 ± 3.6, 63.1 ± 6.7, and 230 ± 1 nM, respectively. Compounds 2 and 7 showed only modest A2780 activities, with IC₅₀ values of 2.1 ± 0.3 and 4.9 ± 0.1 mM, respectively, while compounds 3 and 6 had IC50 values >10 mM. Compound 1 also had potent antiproliferative activity against the HCT116 human colon carcinoma cell line, with an IC₅₀ value of 20.5 nM, and compound 4 exhibited modest antiproliferative activity against the A2058 human caucasian metastatic melanoma and MES-SA human uterine sarcoma cell lines, with IC₅₀ values of 4.6 and 4.0 mM, respectively. In the course of work as part of the Madagascar International Cooperative Biodiversity Group (ICBG) program, an ethanol extract of the stems of Cleistanthus boivinianus (Baill.) Müll. Arg. (Phyllanthaceae) was found to have moderate antiproliferative activity against the A2780 ovarian cancer cell line (IC₅₀ 4.5 mg/mL), and was thus selected for evaluation of the presence of novel antiproliferative agents. The genus Cleistanthus is native to Africa, India, and Australia, and comprises approximately 140 species, but only five of these have been investigated chemically: C. collinus, C. patulus, C. schlechteri var. schlechteri, C. gracilis, and C. indochinensis. Arylnaphthalide lignans are major constituents of the genus, while arytetralin, furofuranoid, and dibenzylbutane lignans and terpenoids have also been isolated from them and are known for their cytotoxic properties.