Synthesis and anticancer activity of aminopropoxytriterpenoids
Triterpenoids with aminopropoxy groups in C-28 or C-3 and C-28 positions were synthesized from betulin, erythrodiol, uvaol, oleantriol and betulinic acid N-methylpiperazinylamide by cyanoethylation and the following catalytic hydrogenolysis. Computational estimating activity spectra of the designed compounds pointed out on their probable antineoplastic and proapoptotic activities. Their in vitro cytotoxic activity was evaluated at the National Cancer Institute, USA. Aminopropoxy derivatives of betulin, erythrodiol and oleantriol demonstrated the highest cytotoxic activity toward the most of 60 used tumor cell lines. Bisaminopropoxyerythrodiol revealed in vivo significant antineoplastic activity toward five mouse solid transplantable tumors. The results of in silico investigations and the efficacy of compounds in a broad panel of cell lines in vitro and the activity of bisaminopropoxyerythrodiol on the in vivo tumor models strongly suggest aminopropoxytriterpenoids as promising compounds for further investigation as anticancer agents.
KeywordsSynthesis Triterpenoids Cyanoethylation Aminopropoxy group Cytotoxicity Anticancer activity
This work was supported by the grant to Russian Foundation for Basic Research (Project № 11-03-12144). We thank National Cancer Institute for screening of compounds 6, 7, 9, 10, 13, 14, 16–18, 20 on human cancer cell lines. Spectroscopic studies were carried out using equipment available at the “Chemistry” User Facilities Center, Ufa Institute of Chemistry of Russian Academy of Sciences.
- Filimonov DA, Poroikov VV (2006) Prediction of biological activity spectra for organic compounds. Zh Ross Khim J 50:66–75Google Scholar
- Geran RI, Greenberg NH, Macdonald MM, Schumacher AM, Abbott BS (1972) Protocols for screening chemical agents and natural products against animal tumors and other biological systems. Cancer Chemother Rep 3:1–91Google Scholar
- Kazakova OB, Smirnova IE, Do Tkhi Tkhu H, Nguen Tkhankh Tra, Apryshko GN, Zhukova OS, Medvedeva NI, Nazyrov TI, Tret’yakova EV, Chudov IV, Ismagilova AF, Suponitsky KY, Kazakov DV, Safarov FE, Tolstikov GA (2013) Synthesis, structure, and pharmacological activity of (7R,8S)-epoxy-(13R,17R)-trioxolane abietic acid. Russ J Bioorg Chem 39:202–211CrossRefGoogle Scholar
- Liu X, Han X, Lin Y, Li Y, Li Q (2015) Influence of betulin in proliferation and apoptosis of human colon cancer SW480 cells. J Jilin Univ Med Edit 41:39–43Google Scholar
- Monks A, Scudiero D, Skehan P, Shoemaker R, Paull KD, Vistica D, Hose C, Langley J, Cronise P, Vaigro-Wolff A, Gray-Goodrich M, Campbell H, Mayo J, Boyd MJ (1991) Feasibility of a high-flux anticancer drug screen using a diverse panel of cultured human tumor cell lines. Nat Cancer Inst 183:757–766CrossRefGoogle Scholar
- Parra A, Martin-Fonseca S, Rivas F, Reyes-Zurita FJ, Medina-O’Donnell M, Rufino-Palomares EE, Martinez A, Garcia-Granados A, Lupiañez JA, Albericio F (2014) Solid-phase library synthesis of bi-functional derivatives of oleanolic and maslinic acids and their cytotoxicity on three cancer cell lines. ACS Comb Sci 16:428–447PubMedCrossRefGoogle Scholar
- Treshalina EM, Jukova OS, Gerasimova GK, Andronova NV, Garin AM (2012) In: Guide to carrying out preclinical researches of medicines. Part 1. Ed. A.N. Mironov. Moscow, Grif and Ko, 640Google Scholar
- Weinstein JN, Myers TG, O’Connor PM, Friend SH, Fornace AJ Jr, Kohn KW, Fojo T, Bates SE, Rubinstein LV, Anderson NL, Buolamwini JK, van Osdol WW, Monks AP, Scudiero DA, Sausville EA, Zaharevitz DW, Bunow B, Viswanadhan VN, Johnson GS, Wittes RE, Paull KD (1997) An information-intensive approach to the molecular pharmacology of cancer. Science 275:343–349PubMedCrossRefGoogle Scholar