Cytotoxic alkaloids from Pogonopus tubulosus: G2/M cell cycle arrest and inhibition of DNA topoisomerase IIα by isotubulosine.

Abstract

Phytochemical investigation of Pogonopus tubulosus trunk led to the isolation of isotubulosine and alangiside, tetrahydroisoquinoline indolic monoterpene alkaloids reported here for the first time for the family Rubiaceae and the genus Pogonopus, respectively. Isotubulosine proved cytotoxic against MCF‐7, PC‐3, 786‐0, HT‐29, and HL‐60 human cancer cell lines, with GI50 values ranging from 5.26 to 20.61 μM, in addition to causing G2/M arrest, possibly by inhibiting DNA topoisomerase IIα. Alangiside showed weak cytotoxicity against MCF‐7 and HL‐60 and proved inactive against PC‐3, HT‐29, and 786‐0 cell lines, with no sign of apoptosis. The alkaloid structures were established on the basis of 1D‐ and/or 2D‐NMR, optical rotation, and HR ESIMS data. Complete 1H NMR assignments of isotubulosine were also performed, using 1H‐1H COSY, HSQC, HMBC, NOESY, and 1H J‐resolved techniques and employing experimental and calculated values of homonuclear coupling constants based on the lowest energy conformations. The foregoing results provide new information on the cytotoxicity and mechanism of action of tetrahydroisoquinoline indole monoterpene‐type alkaloids and reveal isotubulosine to merit further studies as a potential anticancer agent.