title: Designing new analogs for streamlining the structure of cytotoxic lamellarin natural products.
abstract: Despite the therapeutic potential of marine-derived lamellarin natural products, their preclinical development has been hampered by their lipophilic nature, causing very poor aqueous solubility. In order to develop more drug-like analogs, their structure was streamlined in this study from both the cytotoxic activity and lipophilicity standpoints. First, a modified total synthetic route was successfully devised to construct a library of 59 systematically designed lamellarin analogs, which were then subjected to cytotoxicity and log P determinations. Along with the 25 first-generation lamellarins previously synthesized in our laboratory, the structure-activity and structure-lipophilicity relationships were extensively evaluated. Our results clearly indicated the additional structural requirements around the lamellarin skeleton which, when combined with those reported previously, can provide invaluable guidance for further modifications to increase the aqueous solubility of these compounds.
authors.affiliation: Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, Laksi, Bangkok 10210 (Thailand).
authors.forename: Kassrin
authors.initials: K
authors.lastname: Tangdenpaisal
authors.forename: Rattana
authors.initials: R
authors.lastname: Worayuthakarn
authors.forename: Supatra
authors.initials: S
authors.lastname: Karnkla
authors.forename: Poonsakdi
authors.initials: P
authors.lastname: Ploypradith
authors.forename: Pakamas
authors.initials: P
authors.lastname: Intachote
authors.forename: Suchada
authors.initials: S
authors.lastname: Sengsai
authors.forename: Busakorn
authors.initials: B
authors.lastname: Saimanee
authors.forename: Somsak
authors.initials: S
authors.lastname: Ruchirawat
authors.forename: Montakarn
authors.initials: M
authors.lastname: Chittchang
mesh_terms: D000470:Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D006801:Humans; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D000470:Alkaloids; D000970:Antineoplastic Agents
keywords: cytotoxicity; lamellarins; lipophilicity; pyrrole alkaloids; structure-activity relationships