Design, synthesis, and biological evaluation of novel pyridine acid esters of podophyllotoxin and esters of 4′-demethylepipodophyllotoxin

Abstract

Podophyllotoxin and related analogs present numerous challenges associated with optimal antitumor activity and severe unpredictable toxicity. In the course of our ongoing investigation of quantitative structure-activity relationships to find biorational antitumor drugs, two series of pyridine acid ester derivatives of podophyllotoxin and 4 0 -demethylepipodophyllotoxin have been prepared by reacting the corresponding pyridine acids with the hydroxyl group of podophyllotoxin and 4 0 -demethyl epipodophyllotoxin in the presence of dimethylaminopyridine (DMAP) and N,N-dicyclohexylcarbodiimde (DCC). The structures of the compounds were extensively characterized by using 1 H-nuclear magnetic resonance, mass spectroscopy, infrared, and elemental analysis and evaluated for their in vitro cytotoxicity on two neoplastic cell lines (P-388 murine leukemia, A-549 human lung carcinoma) using a MTT-based assay, the results indicated significantly higher efficacy of these compounds in comparison with the prototypical inhibitor etoposide. On the basis of the preliminary biological testing results, it suggested that the cytotoxic activity of OCH 3 at C-4 0 is more potent than that of its demethylated analogs and the podophyllotoxin substitution at C-4 may be optimal for synthesizing more potent cytotoxic compounds.

Pyridine Based Antitumour Compounds Acting at the Colchicine Site

“…[69,70] Similar results have been observed after the introduction of pyridine esters on the hydroxyl group of podophyllotoxin (4). [64,71] One of the earliest aza-podophyllotoxin examples was the conversion of the aryltetralin lactone into an aryltetrahydroisoquinoline cyclic carbamate by substitution of the easily epimerized C2 carbon by a nitrogen atom, thus preventing the inactivation to cis lactones of the picropodophyllin series. [72,73] Despite favorable initial findings, the focus soon turned to dual topoisomerase I and II targeting compounds such as azatoxin, although this route seems to have been abandoned.…”

“…(19). Rationale for the design of combretastatin A-4 (5) and ABT-751 (11) hybrids and structures of the related non tubulin inhibitors HMN-176 (66), its prodrug HMN-214 (65) and indisulam (64).…”

Antitumor activity of a novel dual functional podophyllotoxin derivative involved PI3K/AKT/mTOR pathway

“…Therefore, new topoisomerases inhibitors that have lower toxicity are still required. In view of Topo II inhibition by DMEP, a number of structural modifications at position 4 in DMEP have been conducted, including esterification and amination [5,8–10,12]). For esterification, the carboxyl group was linked to either aromatic rings or non-aromatic rings, and an improved anti-proliferative effect was achieved compared to that of DMEP or ETO at the cell level [5].…”

“…Etoposide is a podophyllotoxin (Ptox) derivative isolated from the Podophyllum species [3], but severe side-effects and multidrug resistance (MDR) often result in treatment failure. To overcome the current limitations, numerous approaches have been made to modify the structure of Ptox [4], including esterification and amination at position 4 to produce 4′-demethylepipodophyllotoxin (DMEP) [5], C-S bond modified aromatic heterocyclic podophyllum derivatives [6], acyl thiourea derivatives of epipodophyllotoxin [7], pyridine acid ester derivatives of Ptox [8], halogen-containing aniline Ptox derivatives [9], and combination of 5-Fu with DMEP derivatives [10]. These modifications were achieved using a molecular hybridization strategy [11,12], and some of the derivatives displayed much better cytotoxic activity than etoposide at the cellular level.…”

Fast and Green Synthesis of 3-Cyano-8-Methyl-2-Oxo-4-Substituted 1,2,5,6,7,8-Hexahydroquinolines

“…Pyridines, quinolines, and tetrahydroquinolines have attracted attention as versatile chemotherapeutic agents due to their antimicrobial [3, 4], antitubercular [5-8], antiamoebic [9-11], antiparasitic [12-14], and antiviral [15,16] properties. Various pyridines and quinolines have antineoplastic [17,18], cytotoxic [19,20], antiproliferative [21,22] activity and other biological properties [23,24]. Cyanopyridine derivatives are of interest because of their confirmed anticancer and antiviral properties [25,26].…”