Synthesis and cytotoxicity evaluation of olivacine-indole hybrids tethered by alkyl linkers

Abstract

In this work, eleven new derivatives were prepared of the alkaloid olivacine (1), which was isolated from the bark of Aspidosperma australe. These compounds (7a–k) are hybrids of olivacine and indoles or carbazole, tethered by alkyl chains of variable lengths (C-4, C-5 or C-6). Compounds 7a–k showed increased cytotoxicity towards a panel of four cell lines. The subcellular localization of olivacine and of the synthetic derivatives was studied by fluorescence microscopy. The cycles of K562 cells exposed to olivacine or compounds 7a–k were analysed by flow cytometry, and showed, for some of the new derivatives, a different profile of cell distribution among the phases of the cycle when compared to olivacine, which is indicative of lysosomal apoptosis.

Graphical Abstract

Keywords:

• Olivacine
• hybrid compounds
• cytotoxic activity
• Aspidosperma australe

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

We are grateful to Dr. Nahuel Schenone, Mr. Javier Unisony and all the staff at the C.I.A.R. for their help and the kind permission to use their facilities (transportation, housing and laboratory) during our field trips to Misiones. Research at UMYMFOR-FCEN-UBA was supported by grants from CONICET to JAP (PIP 2014-2016 N° 11220130100523CO), UBA (UBACyT 2014-2017 N° 20020130100457BA) and ANPCyT (PICT 2014-2063). Work at CIPYP was supported by a grant from CONICET (PIP 0237, to AGC). GMDV, EA, AGC and JAP are researchers of CONICET. CMPD and GC thank CONICET for doctoral fellowships, while MC thanks INC for a student fellowship.