Structure Modification and Metabolic Pathway Optimizations of Anticancer Drugs

Yuchen Zhang

doi:10.54097/c0mbhq95

Authors

Yuchen Zhang

DOI:

https://doi.org/10.54097/c0mbhq95

Keywords:

Anticancer drugs, Structural modification, Metabolic pathway optimization, Toxic metabolites, Personalized therapy.

Abstract

Anti-cancer drugs have a critical position in modern medicine, and their structural modification and metabolic pathway optimization are key strategies to enhance efficacy and safety. Through the introduction of functional groups, changes in molecular ring structure, and covalent and non-covalent modifications, the pharmacokinetic properties of anticancer drugs can be optimized, which can significantly improve their stability, bioavailability, and targeting, as well as reduce toxic side effects. This paper reviews the main strategies for structural modification of anticancer drugs, including functional group addition, molecular ring modification, covalent and non-covalent modification, and analyses the case of metabolic pathway optimization of classical anticancer drugs such as paclitaxel and Adriamycin. These optimizations resulted in significant improvements in the metabolic stability and therapeutic efficacy of the drug. In addition, strategies for the generation and reduction of toxic metabolites, such as reduction of toxic metabolites through the combination of liposome encapsulation, nanoparticle modification, and metabolic inhibitors, are discussed in this paper. Despite significant advances in structure modification and metabolism optimization in anticancer drug development, drug metabolism prediction and individual variability are still challenges that need to be addressed. In the future, combining precision medicine, genomics, big data and artificial intelligence technologies, personalized design of anti-cancer drugs and optimization of metabolic pathways are expected to achieve more efficient and safer cancer treatment options.

Downloads

Download data is not yet available.

References

[1] Kumar, B., Singh, S., Skvortsova, I., & Kumar, V. (2018). Promising Targets in Anti-cancer Drug Development: Recent Updates. Current medicinal chemistry, 24 42, 4729 - 4752. https://doi.org/10.2174/0929867324666170331123648.

[2] Chen, M., Kerkelä, R., & Force, T. (2008). Mechanisms of Cardiac Dysfunction Associated with Tyrosine Kinase Inhibitor Cancer Therapeutics. Circulation, 118, 84 - 95. https://doi.org/10.1161/CIRCULATIONAHA.108.776831.

[3] Murina, A., Uaisova, A., & Ergalieva, A. (2022). ADVANTAGES AND PROSPECTS OF TARGETED THERAPY IN ONCOLOGICAL PRACTICE: A LITERATURE REVIEW. Oncologia i radiologia Kazakhstana. https://doi.org/10.52532/2663 - 4864 - 2022 - 1 - 63 - 70 - 80.

[4] Muhamad, N., & Na-Bangchang, K. (2020). Metabolite Profiling in Anticancer Drug Development: A Systematic Review. Drug Design, Development and Therapy, 14, 1401 - 1444. https://doi.org/10.2147/DDDT.S221518.

[5] Chaudhari, U., Ellis, J., Wagh, V., Nemade, H., Hescheler, J., Keun, H., & Sachinidis, A. (2017). Metabolite signatures of doxorubicin induced toxicity in human induced pluripotent stem cell-derived cardiomyocytes. Amino Acids, 49, 1955 - 1963. https://doi.org/10.1007/s00726-017-2419 - 0.

[6] Khan, K., Akhtar, N., & Minhas, M. (2020). Poloxamer-407-Co-Poly (2-Acrylamido-2-Methylpropane Sulfonic Acid) Cross-linked Nanogels for Solubility Enhancement of Olanzapine: Synthesis, Characterization, and Toxicity Evaluation. AAPS Pharm SciTech, 21. https://doi.org/10.1208/s12249 - 020 - 01694 - 0.

[7] A. Pia P. Kröger, Naomi M. Hamelmann, Alberto Juan, Saskia Lindhoud, Jos M. J. Paulusse*. (2018). Biocompatible Single-Chain Polymer Nanoparticles for Drug Delivery — A Dual Approach, 10, 37, 30946 – 30951.https://pubs.acs.org/doi/10.1021/acsami.8b07450.

[8] Lijun Hu, Sicong Huang, Gengjia Chen, Bo Li, Tan Li, Minzhao Lin, Yongquan Huang, Zecong Xiao*, Xintao Shuai*, Zhongzhen Su*. (2018). Nanodrugs Incorporating LDHA siRNA Inhibit M2-like Polarization of TAMs and Amplify Autophagy to Assist Oxaliplatin Chemotherapy against Colorectal Cancer, 14, 28, 31625 – 31633.https://pubs.acs.org/doi/10.1021/acsami.2c05841.

[9] Jin-Zhi Du, Xiao-Jiao Du, Cheng-Qiong Mao, Jun Wang. (2011). Tailor-Made Dual pH-Sensitive Polymer–Doxorubicin Nanoparticles for Efficient Anticancer Drug Delivery, 133, 44, 17560 – 17563.https://doi.org/10.1021/ja207150n.

[10] Amos B. Smith, III, Keizo Sugasawa, Onur Atasoylu, Chia-Ping Huang Yang, Susan Band Horwitz. (2011). Design and Synthesis of (+)-Discodermolide–Paclitaxel Hybrids Leading to Enhanced Biological Activity, 54, 18, 6319 – 6327.https: //pubs.acs.org/doi/10.1021/jm200692n.

[11] Junhwa Hong, Yijae Lim, Woong Sub Byun, Simin Chun, Suckchang Hong*, Sang Kook Lee*. (2024). Evo312: An Evodiamine Analog and Novel PKCβI Inhibitor with Potent Antitumor Activity in Gemcitabine-Resistant Pancreatic CancerEun Seo Bae, 67, 17, 14885 – 14911.https://doi.org/10.1021/acs.jmedchem.4c00213.

[12] Jinyan Lin, Yang Li, Yanxiu Li, Hongjie Wu, Fei Yu, Shuifan Zhou, Liya Xie, Fanghong Luo, Changjian Lin, Zhenqing Hou, (2015). Drug/Dye-Loaded, Multifunctional PEG–Chitosan–Iron Oxide Nanocomposites for Methotraxate Synergistically Self-Targeted Cancer Therapy and Dual Model Imaging, 7, 22, 11908 – 11920.https://pubs.acs.org/doi/10.1021/acsami.5b01685.

[13] Peter S. Dragovich*. (2022). Antibody–Drug Conjugates for Immunology, 65, 6, 4496 – 4499.https://pubs.acs.org/doi/10.1021/acs.jmedchem.2c00339.

[14] Advait Shetty, Prashanth K.B. Nagesh, Saini Setua, Bilal B. Hafeez, Meena Jaggi, Murali M. Yallapu*, Subhash C. Chauhan*. (2020). Novel Paclitaxel Nano formulation Impairs De Novo Lipid Synthesis in Pancreatic Cancer Cells and Enhances Gemcitabine Efficacy, 5, 15, 8982 –8991.https://pubs.acs.org/doi/10.1021/acsomega.0c00793.

[15] Xiaohui Wei, Dima Shamrakov, Sioma Nudelman, Sivan Peretz-Damari, Einat Nativ-Roth, Oren Regev, Yechezkel Barenholz. (2018). Cardinal Role of Intraliposomal Doxorubicin-Sulfate Nanorod Crystal in Doxil Properties and Performance, 3, 3, 2508 – 2517.https://pubs.acs.org/doi/10.1021/acsomega.7b01235.

[16] Monish Jain, Junying Fan, Nesrine Z. Batrachia-Hoon Kwon. (2004). Sulfonyl-Containing Aldo phosphamide Analogues as Novel Anticancer Prodrugs Targeted against Cyclophosphamide-Resistant Tumor Cell Lines, 47, 15, 3843 – 3852.https://pubs.acs.org/doi/10.1021/jm0304764.

[17] Yonit Kasherman, Stefan Sturup, Dan Gibson. (2009). Is Glutathione the Major Cellular Target of Cisplatin? A Study of the Interactions of Cisplatin with Cancer Cell Extracts, 52, 14, 4319 – 4328.https://doi.org/10.1021/jm900138u.

[18] Xiaoxiao Yang, Wen Lu, Rodrigo W. Alves de Souza, Qiyue Mao, Dipak Baram, Ravi Tripathi, Gangli Wang, Leo E. Otterbein*, Binghe Wang*. (2024). Metal-Free CO Prodrugs Activated by Molecular Oxygen Protect against Doxorubicin-Induced Cardiomyopathy in Mice. https://pubs.acs.org/doi/10.1021/acs.jmedchem.4c01431.

[19] Monish Jain, Junying Fan, Nesrine Z. Baturay, Chul-Hoon Kwon. (2024). Sulfonyl-Containing Aldo phosphamide Analogues as Novel Anticancer Prodrugs Targeted against Cyclophosphamide-Resistant Tumor Cell Lines, 47, 15, 3843 – 3852.https://pubs.acs.org/doi/10.1021/jm0304764.

[20] Aparajita Ghosh, Ambati Himaja, Swati Biswas, Onkar Kulkarni, Balaram Ghosh*. (2023). Advances in the Delivery and Development of Epigenetic Therapeutics for the Treatment of Cancer, 20, 12, 5981 – 6009.https://pubs.acs.org/doi/10.1021/acs.molpharmaceut.3c00610.

[21] Hans-Jürgen Federsel*. (2009). Chemical Process Research and Development in the 21st Century: Challenges, Strategies, and Solutions from a Pharmaceutical Industry Perspective, 42, 5, 671 – 680.https://pubs.acs.org/doi/10.1021/ar800257.

[22] Mohammed Kaleem, Md. Ali Mujtaba, Nilesh Mahajan*, Sayyed A. Ali, Ali F Almutairy, Danish Mahmood, Md. Khalid Anwer, Mohammad Daud Ali, Sanjay Kumar. (2024). A Comprehensive Review of Various Therapeutic Strategies for the Management of Skin Cance, 9, 9, 10030 – 10048.https://pubs.acs.org/doi/10.1021/acsomega.3c09780.