Compound 5c

Abstract: Four sets of new triterpenoids, were prepared from allobetulon, methyl betulonate, methyl oleanonate, and oleanonic acid. First, a thiocyano substituent was introduced at the C2 of each terpenic 3-oxo derivative, which was followed by cyclization with appropriate ammonium salts to form N-substituted thiazole. All 42 new compounds were tested for their in vitro cytotoxic activity on eight cancer cell lines and two non-cancer fibroblasts. Intermediates 2b, 3b, 5b, and 5c were best with IC50 < 10 μM to CCRF-CEM cells (e.g. 3b, IC50 =2.9 μM) as well as thiazoles 5f (9.7 μM) and 5k (11.4 μM). Compound 5c leads to accumulation of cells in the G2 phase of the cell cycle and inhibits RNA/DNA synthesis significantly at 1 × IC50. The G2/M cell cycle arrest probably corresponds to the DNA/RNA synthesis inhibition, similarly to actinomycin D. Compound 5c is new, active, has high therapeutic index and is the most promising for future drug development. Compounds 3b and 3c inhibited nucleic acid synthesis only at 5 × IC50. We assume that in 3b and 3c (unlike in 5c) DNA/RNA inhibition is a non-specific event and unknown primary cytotoxic target is activated at 1 × IC50 or lower concentration.
Introduction …show more content…
They often have many interesting biological activities such as anti-inflammatory,1,2 antibacterial,3,4 antiviral,5,6 antiprotozoal,7,8 anti-cancer, 9,10 and anti-hypoglycemic.11,12 However, in many cases the effective concentrations of most of the natural triterpenoids are not low enough for their therapeutic use. In addition, their solubility in water is low, which causes insufficient bioavailability. As a result, it is necessary to focus on the preparation of triterpenoid derivatives with higher activity, improved pharmacological properties, and more favorable therapeutic