Synthesis and Biological Evaluation of 4β-N-Acetylamino Substituted Podophyllotoxin Derivatives as Novel Anticancer Agents

Abstract

A series of novel podophyllotoxin derivatives obtained by 4β-N-acetylamino substitution at C-4 position was designed, synthesized, and evaluated for in vitro cytotoxicity against four human cancer cell lines (EC-9706, HeLA, T-24 and H460) and a normal human epidermal cell line (HaCaT). The cytotoxicity test indicated that most of the derivatives displayed potent anticancer activities. In particular, compound 12h showed high activity with IC 50 values ranging from 1.2 to 22.8 μM, with much better cytotoxic activity than the control drug etoposide (IC 50 : 8.4 to 78.2 μM). Compound 12j exhibited a promising cytotoxicity and selectivity profile against T24 and HaCaT cell lines with IC 50 values of 2.7 and 49.1 μM, respectively. Compound 12g displayed potent cytotoxicity against HeLA and T24 cells with low activity against HaCaT cells. According to the results of fluorescence-activated cell sorting (FACS) analysis, 12g induced cell cycle arrest in the G2/M phase accompanied by apoptosis in T24 and HeLA cells. Furthermore, the docking studies showed possible interactions between human DNA topoisomerase IIα and 12g. These results suggest that 12g merits further optimization and development as a new podophyllotoxin-derived lead compound.

Chemistry and Biology of Podophyllotoxins: An Update

“…[60] Utilizing PPT and 4'-demethylpodophyllotoxin as precursors, a series of new PPT derivatives (159 a-m and 160 a-g) were synthesized by Wei et al Compounds 159 e-g showed outstanding activities against partial cancer cells and could induce apoptosis. [61] In summary, the chemical structures of promising derivatives against different cell lines were presented in Table 1.…”

“…According to the structure-activity relationships (SARs) of PPT (Figure 8), the aryl tetralin skeleton was necessary for anticancer activity. [61] Previous structural modifica- tions of the A-ring of PPT resulted in derivatives with lower activity than PPT. And almost no modification of the A ring has been reported in recent years, indicating that the dioxolane ring (A ring) of PPT was essential for anticancer activities.…”

“…[55] One or more amino groups introduced at the C-4 position can improve the water solubility of the drug and reduce the toxic effects without diminishing anticancer effects. [61] The derivatives with C-4β conformation exhibited increased antitumor activities and reduced toxic effects. [107] The integrity of the D ring (trans-lactone ring) seemed not closely related to the maintenance of anticancer activities.…”

“…Synthesis of compounds 139 a-139 l, 140 a-140 i, 141 a-141 k, 142 a-142 q and 143 a-143 e. [50][51][52][53] Scheme 17. Synthesis of compounds 154 a-i, 156 a-l, 159 a-m, and 160 a-g. [59][60][61]…”

Synthetic and Naturally Occurring Heterocyclic Anticancer Compounds with Multiple Biological Targets

“…Other genera such as Jeffersonia , Diphylleia , and Dysosma (Family Berberidaceae), Catharanthus (Apocynaceae), Polygala (Polygalaceae), Anthriscus (Apiaceae), Linun (Linaceae), Hyptis (Verbenaceae), Teucrium , Nepeta and Thymus (Labiaceae), Thuja , Juniperus , Callitris and Thujopsis (Cupressaceae), Cassia (Fabaceae), Haplophyllum (Rutaceae), Commiphora (Burseraceae), and Hernandia (Hernandiaceae) have also been reported to produce podophyllotoxin (PTOX) and its derivatives as well as other lignans [ 185 ]. Podophyllotoxin, 132 and deoxy-podophyllotoxin, 133 , both cyclolignans from the Anthriscus and Juniperus genera have shown excellent therapeutic effect on cancer cells with tubulin, and DNA topoisomerase II as potential targets ( Figure 26 ) [ 186 , 187 ].…”