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Marine Natural Products as Models to Circumvent Multidrug Resistance
Solida Long1, Emília Sousa2,3, Anake Kijjoa4,5
1Laboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Porto 4050-313, Portugal. up201502099@ff.up.pt.
Abstract:
Multidrug resistance (MDR) to anticancer drugs is a serious health problem that in many cases leads to cancer treatment failure. The ATP binding cassette (ABC) transporter P-glycoprotein (P-gp), which leads to premature efflux of drugs from cancer cells, is often responsible for MDR. On the other hand, a strategy to search for modulators from natural products to overcome MDR had been in place during the last decades. However, Nature limits the amount of some natural products, which has led to the development of synthetic strategies to increase their availability. This review summarizes the research findings on marine natural products and derivatives, mainly alkaloids, polyoxygenated sterols, polyketides, terpenoids, diketopiperazines, and peptides, with P-gp inhibitory activity highlighting the established structure-activity relationships. The synthetic pathways for the total synthesis of the most promising members and analogs are also presented. It is expected that the data gathered during the last decades concerning their synthesis and MDR-inhibiting activities will help medicinal chemists develop potential drug candidates using marine natural products as models which can deliver new ABC transporter inhibitor scaffolds.
Insights
Marine natural products can inhibit P-glycoprotein (P-gp), a key factor in multidrug resistance (MDR) to cancer drugs. Synthetic strategies enhance availability of these compounds, offering new models for developing MDR-inhibiting drug candidates.
Area of Science:
- Marine natural products
- Medicinal chemistry
- Drug discovery
Background:
- Multidrug resistance (MDR) is a major challenge in cancer therapy, often caused by P-glycoprotein (P-gp) efflux pumps.
- Natural products offer a promising avenue for discovering MDR modulators, but supply limitations necessitate synthetic approaches.
Purpose of the Study:
- To review marine natural products and their derivatives with P-gp inhibitory activity.
- To highlight structure-activity relationships and synthetic pathways for promising compounds.
Main Methods:
- Literature review of marine natural products with P-gp inhibitory activity.
- Summary of established structure-activity relationships.
- Presentation of synthetic pathways for key marine compounds and analogs.
Main Results:
- Identified various marine natural product classes (alkaloids, sterols, polyketides, terpenoids, diketopiperazines, peptides) exhibiting P-gp inhibitory effects.
- Detailed structure-activity relationships for these compounds.
- Outlined synthetic strategies for producing potent MDR inhibitors.
Conclusions:
- Marine natural products serve as valuable models for developing novel anticancer drugs that overcome MDR.
- Further research into synthesis and activity can lead to new therapeutic agents targeting ABC transporters.
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