Synthesis and Cytotoxic Activity of Novel Betulin Derivatives Containing Hydrazide-Hydrazone Moieties

Abstract

A series of novel betulin derivatives containing hydrazide-hydrazone moieties were synthesized. All compounds were evaluated for their cytotoxicity against four human carcinoma cell lines (HepG2, A549, MCF-7 and HCT-116) and a normal human gastric epithelial cell line (GES-1). Among them, compound 6i was the most potent against HepG2 and MCF-7 cell lines, with IC50 values of 9.27 and 8.87 μM, respectively. The results suggest that the incorporation of a hydrazide-hydrazone side chain at the C-28 position of betulin is beneficial for compounds to display significant cytotoxicity. Compound 6i may be used as a promising skeleton for antitumor agents with improved efficacy.

Synthesis, Pharmacological Properties, and Potential Molecular Mechanisms of Antitumor Activity of Betulin and Its Derivatives in Gastrointestinal Cancers

“…The reactions of the aldehyde group with amine derivatives were also used in the synthesis of two further series of derivatives ( Figure 16 ). In the first case, betulinic aldehyde reacted with hydrazides of various structures, obtaining derivatives containing hydrazide-hydrazone moieties 22a–i [ 80 ]. Another series of compounds, 23a–o , was created in the reaction of betulinic aldehyde hydrazone with aldehydes [ 81 ].…”

“…Studies of the cytotoxic effect on HCT-116 cells conducted for this group of derivatives showed that the hydrazide and hydrazine derivatives containing a 4-trifluoromethylphenyl substituent ( 22d and 23h ) were the most active (IC 50 equal to 13.70 and 12.55 μM). Derivatives containing the pyridine ring 22i (IC 50 = 9.30 μM) and 23k (IC 50 = 9.32 μM) had the strongest effects on human hepatocellular carcinoma cells (HepG2) [ 79 , 80 , 81 ].…”

“… Structure of derivatives of betulin with hydrazide–hydrazone moieties 22a–i [ 80 ] and 23a–o [ 81 ]. …”

“…Phenyl derivatives 18b and 19b showed no activity against the tested cancer lines [78]. The transformation of BE into betulinic aldehyde opened a new direction in the synthesis of derivatives whose structure resulted from the reactivity of the formyl group [79][80][81]. In the reaction of betulinic aldehyde with hydrazine hydrate, carried out in an ethanol solution at a temperature of 40 °C, betulin hydrazone is formed.…”

Design, Synthesis, and Anticancer Evaluation of Novel Tetracaine Hydrazide-Hydrazones

“…Various pharmacological activities were investigated by many researchers such as antimicrobial , and anticancer. , Also, hydrazide-hydrazone derivatives have been reported to have diverse pharmacological activities, especially anticancer activity. − Han et al synthesized novel hydrazide-hydrazone molecules and controlled the anticancer activity on the HepG2 cell line . Anticancer activity studies of hydrazide-hydrazone molecules have been observed in many studies, and it has been determined that hydrazide-hydrazone molecules show activity against Colo-205 and HegG2 cell lines. − …”