Synthesis and Cytotoxic Activity of Triterpenoid Thiazoles Derived from Allobetulin, Methyl Betulonate, Methyl Oleanonate, and Oleanonic Acid

Abstract

A total of 41 new triterpenoids were prepared from allobetulone, methyl betulonate, methyl oleanonate, and oleanonic acid to study their influence on cancer cells. Each 3-oxotriterpene was brominated at C2 and substituted with thiocyanate; subsequent cyclization with the appropriate ammonium salts gave N-substituted thiazoles. All compounds were tested for their in vitro cytotoxic activity on eight cancer cell lines and two non-cancer fibroblasts. 2-Bromoallobetulone (2 b) methyl 2-bromobetulonate (3 b), 2-bromooleanonic acid (5 b), and 2-thiocyanooleanonic acid (5 c) were best, with IC values less than 10 μm against CCRF-CEM cells (e.g., 3 b: IC =2.9 μm) as well as 2'-(diethylamino)olean-12(13)-eno[2,3-d]thiazole-28-oic acid (5 f, IC =9.7 μm) and 2'-(N-methylpiperazino)olean-12(13)-eno[2,3-d]thiazole-28-oic acid (5 k, IC =11.4 μm). Compound 5 c leads to the accumulation of cells in the G phase of the cell cycle and inhibits RNA and DNA synthesis significantly at 1×IC . The G /M cell-cycle arrest probably corresponds to the inhibition of DNA/RNA synthesis, similar to the mechanism of action of actinomycin D. Compound 5 c is new, active, and nontoxic; it is therefore the most promising compound in this series for future drug development. Methyl 2-bromobetulonate (3 b) and methyl 2-thiocyanometulonate (3 c) were found to inhibit nucleic acid synthesis only at 5×IC . We assume that in 3 b and 3 c (unlike in 5 c), DNA/RNA inhibition is a nonspecific event, and an unknown primary cytotoxic target is activated at 1×IC or lower concentration.

A Synthetic Approach for the Rapid Preparation of BODIPY Conjugates and their use in Imaging of Cellular Drug Uptake and Distribution

“…General technical information is available in the Supporting Information and is analogous to our previous publications . Note that the yields of the final conjugates ( 24 – 33 , usually between 10–30 %) are calculated as overall yields of the entire synthetic procedure between compound 20 and the final product in Scheme .…”

Effective synthesis of novel furan-fused pentacyclic triterpenoids via anionic 5-exo dig cyclization of 2-alkynyl-3-oxotriterpene acids

“…The residue was purified by column chromatography on SiO2 with hexane/EtOAc (30:1) as an eluent to give a final compound: 14a-g, 17 Methyl 2α-(3,4,5-trimethoxyphenylpropynyl)-3-oxolup-20(29)en-28-oate (14f) 74 (s, 3H, H-30), 1.25, 1.14, 1.03,1.01, 0.88 (all s, 3H each, H-23-H-27). 13 C 5'-(3,4,5-trimethoxybenzyl)furano[3,2-b]lup-20(29)-en-28-oate (15f 71 (s, 3H, H-30 compound 11a-13a, 15a-f, 18a or 20a (0.4 mmol) in DMF (3 mL). The reaction mixture was heated under reflux for 5 h (monitoring by TLC), diluted with water (2 mL), and neutralized with 5% HCl (aq).…”

“…Chlorobenzyl)furano[3,2-b]lup-20(29)-en-28-oic acid (16c). Colorless crystals (45% 5'-(4-Fluorobenzyl)furano[3,2-b]lup-20(29)-en-28-oic acid (16d) 13 C NMR (see Table 2). Anal.…”

“…Among them, considerable attention has been given to heterocyclic triterpenoids with various nitrogen, sulfur, and oxygen heterocycles. [9][10][11][12][13][14][15][16][17][18] The biological activity of triterpenoid heterocycles are promising and many of them have been studied as antitumor, [9][10][11][12][13] antiosteoporosis, 14,15 antiinflammatory 16 and antileishmanial agents. 17,18 Among this group of potentially biologically active compounds, furan triterpenoid derivatives have not been reported in the literature.…”

“…С NMR spectra of furan-fused triterpenoids adequately reflected their structure. Indeed, the 13 С NMR spectrum of compound 11a exhibited no signals for the acetylene and carbonyl carbon atoms, indicating that these functional groups of the initial methyl betulonate 8 were transformed in the intramolecular cyclization. Apart from the characteristic signal for the quaternary С-20 carbon atom (150.57 ppm), the spectrum exhibited three new signals for quaternary carbon atoms (DEPT, HSQC) at 113.68, 149.57, and 154.44 ppm, which were assigned to С-2, С-5', and С-3, respectively.…”