Structure, synthesis and biological activities of biflavonoids isolated from Ochna serrulata (Hochst.) Walp.
The phytochemistry of Ochna serrulata (Hochst.) Walp. was investigated for the first time; two new dimeric chalcones (5-deoxyurundeuvine C and serrulone A) and two new biflavonoid derivatives (4,4’,7-tri-O-methylisocampylospermone A and 4”’-de-Omethylafzelone A) were isolated. These compounds were isolated along with the known compounds lophirone A, afzelone B, campylospermone A, isocampylospermone A, ochnaflavone, 2”,3”-dihydroochnaflavone, lophirone C, psilosin, 3’-O-methylpsilosin, a cyanoglucoside, epicatechin, (2’,4’- dihydroxyphenyl)acetic acid, methyl (2’,4’-dihydroxyphenyl)acetate, irisolone 4’- methyl ether, iriskumaonin 3’-methyl ether, 3',4'-dimethoxy-6,7-methylenedioxyisoflavone, lophirone L, syringaresinol and 16α,17-dihydroxy-entkauran-19-oic acid. The growth inhibitory effect of these compounds was evaluated against three cancer cell line panel of TK 10 (renal), UACC62 (melanoma) and MCF7 (breast) using a sulforhodamine B (SRB) assay. Ochnaflavone and 3’-methoxypsilosin demonstrated selectivity and only inhibited the growth of melanoma cancer cells. However, ochnaflavone showed higher activity by totally inhibiting the growth of melanoma cancer cells at 12.91 μM, whereas, 3’-O-methylpsilosin has this effect at a concentration of 14.11 μM. Lophirone C, a dimeric chalcone, demonstrated the highest cytotoxic activity amongst all isolated compounds against renal, melanoma and breast cancer cells with TGI at 35.63 μM, 11.67 μM and 30.35 μM, respectively. Lophirone A, a rearranged biflavonoid, showed TGI against these cancer cells at 58.96 μM, 26.23 μM and 40.01 μM, respectively. The rest of the compounds showed no significant cytotoxicity against the three cancer cells. The new biflavonoid, 4,4’,7-tri-O-methylisocampylospermone A demonstrated the highest antimalarial activity against chloroquine-resistant strains of Plasmodium falciparum (FCR-3) with IC50 of 11.46 μM, followed by ochnaflavone (17.25 μM). iv Serrulone A (26.52 μM), lophirone A (29.78 μM), 5-deoxyurundeuvine C (31.07 μM), lophirone C (35.31 μM), 4”’-de-O-methylafzelone A (38.43 μM), afzelone B (39.54 μM), irisolone 4’-methyl ether (40.72 μM) and syringaresinol (42.66 μM) were moderately active. The following compounds exhibited the lowest antimalarial activity, 2”,3”-dihydroochnaflavone (61.86 μM), iriskumaonin 3’-O-methyl ether (93.69 μM),3’- O-methylpsilosin (106.35 μM) and16α,17-dihydroxy-ent-kauran-19-oic acid (106.48 μM). Owing to the observed and reported biological/pharmacological activity, ochnaflavone (an ether-linked biflavone consisting of apigenin and luteolin moieties) was selected for synthetic studies. An older method, nucleophilic aromatic substitution (SNAr) was successfully applied in the construction of the diary ether. Oxidative ring cyclization of the ether-linked dimeric chalcone was achieved by using heated pyridine and iodine. The two methods can be extended further in the synthesis of other novel biflavones with ether linkage.