title: Marine Natural Products as Models to Circumvent Multidrug Resistance.
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.
authors.affiliation: Laborat&#243;rio de Qu&#237;mica Org&#226;nica e Farmac&#234;utica, Departamento de Ci&#234;ncias Qu&#237;micas, Faculdade de Farm&#225;cia, Universidade do Porto, Porto 4050-313, Portugal. up201502099@ff.up.pt.
authors.forename: Solida
authors.initials: S
authors.lastname: Long
authors.affiliation: Laborat&#243;rio de Qu&#237;mica Org&#226;nica e Farmac&#234;utica, Departamento de Ci&#234;ncias Qu&#237;micas, Faculdade de Farm&#225;cia, Universidade do Porto, Porto 4050-313, Portugal. esousa@ff.up.pt.|Interdisciplinary Centre of Marine and Environmental Research (CIIMAR), Porto 4050-123, Portugal. esousa@ff.up.pt.
authors.forename: Emília
authors.initials: E
authors.lastname: Sousa
authors.affiliation: Interdisciplinary Centre of Marine and Environmental Research (CIIMAR), Porto 4050-123, Portugal. ankijjoa@icbas.up.pt.|Instituto de Ci&#234;ncias Biom&#233;dicas Abel Salazar (ICBAS), Universidade do Porto, Porto 4050-123, Portugal. ankijjoa@icbas.up.pt.
authors.forename: Anake
authors.initials: A
authors.lastname: Kijjoa
authors.affiliation: Laborat&#243;rio de Qu&#237;mica Org&#226;nica e Farmac&#234;utica, Departamento de Ci&#234;ncias Qu&#237;micas, Faculdade de Farm&#225;cia, Universidade do Porto, Porto 4050-313, Portugal. madalena@ff.up.pt.|Interdisciplinary Centre of Marine and Environmental Research (CIIMAR), Porto 4050-123, Portugal. madalena@ff.up.pt.
authors.forename: Madalena M M
authors.initials: MM
authors.lastname: Pinto
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000470:Alkaloids / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D001688:Biological Products / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D054659:Diketopiperazines / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects* / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D061065:Polyketides / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D013261:Sterols / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013729:Terpenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D000470:Alkaloids; D000970:Antineoplastic Agents; D001688:Biological Products; D054659:Diketopiperazines; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D010455:Peptides; D061065:Polyketides; D013261:Sterols; D013729:Terpenes
keywords: ABC transporters; P-glycoprotein modulators; marine natural products; multidrug resistance (MDR); structure activity relationship (SAR); synthesis