Synthesis and Biological Evaluation of New Podophyllic Aldehyde Derivatives with Cytotoxic and Apoptosis-Inducing Activities

Abstract

Several series of nonlactonic podophyllic aldehyde analogues were prepared and evaluated against several human tumor cell lines. They had different combinations of aldehyde, imine, amine, ester, and amide functions at C-9 and C-9' of the cyclolignan skeleton. All the compounds synthesized showed cytotoxicity levels in the microM range and below. Within the new series tested, compounds having an aldehyde or imine at C-9 and an ester at C-9' were the most potent, with GI(50) values in the nM range, some of them being several times more potent against HT-29 and A-549 carcinoma than against MB-231 melanoma cells. Cell cycle studies and analysis of the microtubule-disrupting capacity have demonstrated the existence of two different mechanisms of cell death induction for compounds with closely related structures.

Synthesis and Anticancer Activity of Glucosylated Podophyllotoxin Derivatives Linked via 4β-Triazole Rings

“…Among them, five semisynthetic derivatives, etoposide (2), teniposide (3), etopophos (4), GL-331 (5) and TOP-53 (6) ( Figure 1) are currently used in the chemotherapy for a variety of cancers, including small-cell lung cancer, non-Hodgkin's lymphoma, leukemia, Kaposi's sarcoma, neurobslastoma and soft tissue sarcoma. These derivatives display binding activity to DNA topoisomerase II during the late S and early G2 cell cycle stages and are potent inhibitors of the enzyme [7][8][9][10][11][12][13][14]. Their anticancer activity proceeds through a mechanism of action entirely different from that of their parent compound podophyllotoxin (1).…”

Design and synthesis of 6,7-methylenedioxy-4-substituted phenylquinolin-2(1H)-one derivatives as novel anticancer agents that induce apoptosis with cell cycle arrest at G2/M phase

“…This mechanism is associated with cell death and sub-G1 apoptotic cell accumulation without any significant cell cycle arrest. 13 Thus, mechanistic studies on 12e are underway in our laboratories.…”

“…Several aldehydes related to this compound but with different configurations have been synthesized and evaluated for cytotoxic activities in neoplastic cell lines. 13,14 These podophyllic aldehyde-related compounds lacked the lactone ring, but maintained cytotoxicity at, or under, micromolar level.…”

A Novel Cytotoxic Conjugate Derived from the Natural Product Podophyllotoxin as a Direct-Target Protein Dual Inhibitor

“…From those studies, the γ-lactone ring of the compound, which was considered an essential part for the cytotoxic activity, was also modified, leading to compounds with interesting profiles of potency and selectivity against several cancer cell lines. This is the case of podophyllic aldehyde ( Figure 1 ), a non-lactonic derivative that showed improved cytotoxic results, reaching potency in the nanomolar range similar to that of the parent compound but with better selectivity than podophyllotoxin towards certain tumor cell lines [ 10 , 11 ]. It shares the same mechanism of action as podophyllotoxin.…”

“…Both fragments can be connected through the C-7 and C-9 positions, respectively, through different linkers. In this case, we chose diamine type spacers, taking advantage of previous experience in the formation of imines in the aldehyde function [ 11 ]. Based on our previous results with hybrids of podophyllotoxin [ 13 ], in this paper, we report the first example of these new hybrids, in which the linker between both fragments is an aromatic diamine.…”