Challenges and potential for improving the druggability of podophyllotoxin-derived drugs in cancer chemotherapy

Covering: up to 2020 As a main bioactive component of the Chinese, Indian, and American Podophyllum species, the herbal medicine, podophyllotoxin (PTOX) exhibits broad spectrum pharmacological activity, such as superior antitumor activity and against multiple viruses. PTOX derivatives (PTOXs) could...

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Published inNatural product reports Vol. 38; no. 3; pp. 47 - 488
Main Authors Zhao, Wei, Cong, Ying, Li, Hong-Mei, Li, Shengying, Shen, Yuemao, Qi, Qingsheng, Zhang, Youming, Li, Yue-Zhong, Tang, Ya-Jie
Format Journal Article
LanguageEnglish
Published England Royal Society of Chemistry 01.03.2021
Subjects
Anticancer properties
antineoplastic activity
Antineoplastic Agents - therapeutic use
Antitumor activity
bioactive compounds
Bioavailability
Biocompatibility
Cancer therapies
cancer therapy
Cell cycle
Central nervous system
Chemotherapy
Coronaviruses
COVID-19
COVID-19 infection
Cytokine storm
Cytokines
Deoxyribonucleic acid
DNA
DNA damage
DNA topoisomerase (ATP-hydrolysing)
Drug Design
Drug development
Drug resistance
drug therapy
Drugs
Etoposide
Growth factors
Health services
Herbal medicine
herbal medicines
Humans
Insulin
insulin-like growth factor I receptor
Lung cancer
lung neoplasms
Neoplasms - drug therapy
Podophyllotoxin
Podophyllotoxin - therapeutic use
Podophyllum
RNA
Small cell lung carcinoma
Teniposide
testes
Testicular cancer
Toxicity
Tubulin
Viral diseases
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Summary:Covering: up to 2020 As a main bioactive component of the Chinese, Indian, and American Podophyllum species, the herbal medicine, podophyllotoxin (PTOX) exhibits broad spectrum pharmacological activity, such as superior antitumor activity and against multiple viruses. PTOX derivatives (PTOXs) could arrest the cell cycle, block the transitorily generated DNA/RNA breaks, and blunt the growth-stimulation by targeting topoisomerase II, tubulin, or insulin-like growth factor 1 receptor. Since 1983, etoposide (VP-16) is being used in frontline cancer therapy against various cancer types, such as small cell lung cancer and testicular cancer. Surprisingly, VP-16 (ClinicalTrials NTC04356690) was also redeveloped to treat the cytokine storm in coronavirus disease 2019 (COVID-19) in phase II in April 2020. The treatment aims at dampening the cytokine storm and is based on etoposide in the case of central nervous system. However, the initial version of PTOX was far from perfect. Almost all podophyllotoxin derivatives, including the FDA-approved drugs VP-16 and teniposide, were seriously limited in clinical therapy due to systemic toxicity, drug resistance, and low bioavailability. To meet this challenge, scientists have devoted continuous efforts to discover new candidate drugs and have developed drug strategies. This review focuses on the current clinical treatment of PTOXs and the prospective analysis for improving druggability in the rational design of new generation PTOX-derived drugs. Natural product podophyllotoxin exhibited superior broad spectrum antitumor and antiviral activity. Over past 30 years, scientists devoted continuous efforts to develop druggability strategies and discover new podophyllotoxin-derived drugs.
Bibliography:Ying Cong started her doctoral study and scientific research under the supervision of Prof. Ya-Jie Tang in 2019. Her doctoral research focuses on the design, synthesis, and discovery of podophyllotoxin leading compounds with high activity and low toxicity by the strategy of specificity-targeting tumor cells or tissues.
Since 2005, Prof. Ya-Jie Tang's group has been committed to the discovery of new podophyllotoxin-derived antitumor drugs. A series of candidate drugs with nanomolar-potency antitumor activity were developed, which were superior to the approved tubulin-targeting antitumor drugs. Compared with the approved topoisomerase II-targeting anti-tumor drugs, other candidate drugs exhibited weaker DNA damage and millimolar-potency (low) toxicity. Prof. Ya-Jie Tang's group also focuses on the biomanufacture of podophyllotoxin-derived drugs in order to solve the problems of complex synthetic steps, enantiomers, environmental pollution
etc.
Associate Prof. Wei Zhao has studied and worked in Prof. Ya-Jie Tang's group to carry out research on the design, synthesis, and druggability of podophyllotoxin-derived drugs based on tubulin, topoisomerase II, or other targets for new drug development since 2007. Based on the study of the drug-tubulin complex crystal structure, a dual-target drug design strategy for podophyllotoxin derivatives was established. A method of tandem biotransformation was designed and developed to modify the molecular structure of podophyllotoxin for the directional synthesis of potential antitumor leading compounds. Wei Zhao is committed to research on druggability of podophyllotoxin derivatives.
during chemical synthesis processes.
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ISSN:0265-0568
1460-4752
1460-4752
DOI:10.1039/d0np00041h