Synthesis and Evaluation of New Podophyllotoxin Derivatives with in Vitro Anticancer Activity

Abstract

A series of novel podophyllotoxin derivatives were designed and synthesized. The cytotoxic activities of these compounds were tested against three tumor cell lines (HeLa, K562, and K562/A02). Most of the derivatives (IC50 = 1-20 μM) were found to have stronger cell growth inhibitory activity than positive control etoposide. Among them, 4β-N-[(E)-(5-((4-(4-nitrophenyl)-piperazin-1-yl)methyl)furan-2-yl)prop-2-en-1-amine]-4-desoxy-podophyllotoxin (9l) demonstrated significant inhibitory activity against HeLa, K562, and K562/A02 cell lines with IC50 values of 7. 93, 6.42, 6.89 μM, respectively.

Podophyllotoxin Isolated from Podophyllum peltatum Induces G2/M Phase Arrest and Mitochondrial-Mediated Apoptosis in Esophageal Squamous Cell Carcinoma Cells

“…Podophyllotoxin (PT) has been used as an herbal drug in traditional folk remedies for preventive and therapeutic applications for more than 1000 years. PT, one of the active cyclolignan compounds extracted from Podophyllum peltatum and P. hexandrum, has been reported to provide beneficial effects in patients with intestinal Ascaris lumbicoides-induced symptoms, venereal warts, lymphoma, and cancers [7,8]. Compelling reports have demonstrated that PT-derived anticancer drugs play a powerful role in inhibiting topoisomerase II activity and inducing apoptosis of several types of cancers, including female-related tumors, non-Hodgkin's lymphomas, and lung cancers [4,8,9].…”

Synthesis and Biological Evaluation of Certain new Cyclohexane-1-carboxamides as Apoptosis Inducers

“…The cyclohexane core generally has enriched the medicinal chemistry armamentarium with several bioactive candidates having diverse biological activities such as antipsychotic 5 , expectorant 6 , anticonvulsant 7,8 , analgesic 9 and anticancer activities [10][11][12] . Etoposide (I) and Teniposide (II) contain cyclohexane moiety in their structures and are used in cancer chemotherapy for the treatment of lung cancer, acute leukemia and lymphoma through a cytotoxic mechanism of DNA-topoisomerase II inhibition [13][14][15] . Moreover, the aminoacyl pharmacophore chain and amide moiety were included in the structural frame of different antitumor compounds, III and IV (Fig.…”

Azapodophyllotoxin Causes Lymphoma and Kidney Cancer Regression by Disrupting Tubulin and Monoglycerols

“…However, its therapeutic use has been restricted due to its high toxicity . Extensive efforts to reduce its toxic effects led to the development of its semisynthetic derivatives etoposide and teniposide, which are currently used in combination cancer chemotherapy but have different mechanisms of action than podophyllotoxin. , Reports on completely synthetic analogues of podophyllotoxins are rather limited due to its highly complex structure. Recently, there has been a growing interest in the development of aza analogues of A that retain key structural aspects and can be synthesized in a single-step, one-pot multicomponent reaction .…”