The antimitotic Podophyllotoxin and its derivatives- recent synthetic advances

: The substantial antimitotic potential of podophyllotoxin and its derivatives has attracted both synthetic and medicinal chemists to expand the chemical space for the subsequent biological evaluation of these compounds. The interest ranges from total synthesis, hemi-synthesis, one-pot synthetic approaches and structure-activity relationship studies. In the first segment of the review, we present recent development in the synthesis of podophyllotoxin and also describe its mode of action. The second section covers the synthesis and the structure-activity relationships of podophyllotoxin derivatives, along with the discussion of important structural features required by the molecule for displaying antimitotic activity. The last part describes the synthesis and biological evaluation of potent 4-aza podophyllotoxin derivatives. This review is of interest to chemists who study natural and synthetic compounds for drug discovery.

Insight Into the Molecular Mechanism of Podophyllotoxin Derivatives as Anticancer Drugs

Podophyllotoxin (PTOX) is a biologically active compound derived from the podophyllum plant, and both it and its derivatives possess excellent antitumor activity. The PTOX derivatives etoposide (VP-16) and teniposide (VM-26) have been approved by the U.S. Food and Drug Administration (FDA) for cancer treatment, but are far from perfect. Hence, numerous PTOX derivatives have been developed to address the major limitations of PTOX, such as systemic toxicity, drug resistance, and low bioavailability. Regarding their anticancer mechanism, extensive studies have revealed that PTOX derivatives can induce cell cycle G2/M arrest and DNA/RNA breaks by targeting tubulin and topoisomerase II, respectively. However, few studies are dedicated to exploring the interactions between PTOX derivatives and downstream cancer-related signaling pathways, which is reasonably important for gaining insight into the role of PTOX. This review provides a comprehensive analysis of the role of PTOX derivatives in the biological behavior of tumors and potential molecular signaling pathways, aiming to help researchers design and develop better PTOX derivatives.

Screening of 20 Pantanal Wetland Plants for Anti-Candida Activity using HPLC-DAD-MS/MS and Bioautography to Characterize Active Compounds

The Pantanal wetland harbors a rich flora with uncharted pharmacological potential. This study evaluated 20 Brazilian Pantanal plants against Candida albicans, C. parapsilosis, C. tropicalis, and C. krusei. Fungal susceptibility was determined by agar diffusion and broth microdilution; active compounds were identified by bioautography and HPLC-DAD-MS/MS. Sesbania virgata, Polygala molluginifolia, and Cantinoa mutabilis extracts and their chloroform and ethyl acetate (EtOAc) fractions exhibited the best activity against all Candida species tested. The EtOAc fraction of P. molluginifolia proved to be more efficient in inhibiting C. parapsilosis and C. krusei growth (Minimum inhibitory concentration of 125 and 62.5 μg/mL, respectively). Bioautography of this fraction revealed two active bands, characterized by HPLC-DAD-MS/MS as a mixture of podophyllotoxin derivatives blumenol, besides some flavonoids. This work demonstrated antifungal potential of P. molluginifolia podophyllotoxin derivatives and the versatility of bioautography with HPLC-DAD-MS/MS to identify the bioactive compounds.

Aryltetralin-type lignan of Podophyllum: a comprehensive review

: Podophyllotoxin is a nonalkaloidtoxin aryltetralin lactone lignan, occurring naturally and extracted from the rhizomes and roots of Podophyllum species. Podophyllotoxin and its derivatives have shown to possess a broad spectrum of pharmacological activities, mainly antineoplastic and antiviral properties. Podophyllotoxin is served as a potential anticancer agent and also the precursor for the chemical synthesis of some clinically important anticancer agents.The chemical modification and pharmacological investigation of podophyllotoxin derivatives have become a concern nowadays. Research interest has been stimulated in the innovation of podophyllotoxin derivatives as the semi-synthetic anticancer agent, especially etoposide and teniposide. Podophyllotoxin and its derivatives are available in several formulations and also found to be effective in combination therapy. This review article aims to provide an overview of the role of podophyllotoxin, its mechanism of action, pharmacological activities, pharmacokinetics, available formulations, and its effects in combination therapy. This article also reviewed the biosynthesis, structure and modifications of podophyllotoxin and its derivatives as an anticancer agent.

Recent advances in the application of podophyllotoxin derivatives to fight against drugresistant cancer cells

: Podophyllotoxins including epipodophyllotoxin derivatives can act on a diverse array of drug targets in cancer cells, and thus possess potential activity against various forms of cancer cell lines including drug-resistant forms. Moreover, several podophyllotoxin derivatives which are represented by etoposide and teniposide have already been approved for the cancer therapy, demonstrating podophyllotoxin moiety is a useful pharmacophore for the discovery of novel anticancer agents. This review reports the recent advances in exploitation of podophyllotoxin derivatives to fight against multidrug-resistant cancer cells. The mechanism of action and structure-activity relationship (SAR) studies are also highlighted.

Tubulin Inhibitors Binding to Colchicine-Site: A Review from 2015 to 2019

Due to the three domains of the colchicine-site which is conducive to the combination with small molecule compounds, colchicine-site on the tubulin has become a common target for antitumor drug development, and accordingly, a large number of tubulin inhibitors binding to the colchicine-site have been reported and evaluated over the past years. In this study, tubulin inhibitors targeting the colchicine-site and their application as antitumor agents were reviewed based on the literature from 2015 to 2019. Tubulin inhibitors were classified into ten categories according to the structural features, including colchicine derivatives, CA-4 analogs, chalcone analogs, coumarin analogs, indole hybrids, quinoline and quinazoline analogs, lignan and podophyllotoxin derivatives, phenothiazine analogs, N-heterocycle hybrids and others. Most of them displayed potent antitumor activity, including antiproliferative effects against Multi-Drug-Resistant (MDR) cell lines and antivascular properties, both in vitro and in vivo. In this review, the design, synthesis and the analysis of the structure-activity relationship of tubulin inhibitors targeting the colchicine-site were described in detail. In addition, multi-target inhibitors, anti-MDR compounds, and inhibitors bearing antitumor activity in vivo are further listed in tables to present a clear picture of potent tubulin inhibitors, which could be beneficial for medicinal chemistry researchers.