title: A comprehensive study of Sansalvamide A derivatives: The structure-activity relationships of 78 derivatives in two pancreatic cancer cell lines.
abstract: We report an extensive structure-activity relationship (SAR) of 78 compounds active against two pancreatic cancer cell lines. Our comprehensive evaluation of these compounds utilizes SAR that allow us to evaluate which features of potent compounds play a key role in their cytotoxicity. This is the first report of 19 new second-generation structures, where these new compounds were designed from the first generation of 59 compounds. These 78 structures were tested for their cytotoxicity and this is the first report of their activity against two pancreatic cancer cell lines. Our results show that out of 78 compounds, three compounds are worth pursuing as leads, as they show potency of 55% in both cancer cell lines. These three compounds all have a common structural motif, two consecutive d-amino acids and an N-methyl moiety. Further, of these three compounds, two are second-generation structures, indicating that we can incorporate and utilize data from the first generation to design potency into the second generation. Finally, one analog is in the mid nanomolar range, and has the lowest IC(50) of any reported San A derivative. These analogs share no structural homology to current pancreatic cancer drugs, and are cytotoxic at levels on par with existing drugs treating other cancers. Thus, we have established Sansalvamide A as an excellent lead for killing multiple pancreatic cancer cell lines.
authors: Department of Chemistry and Biochemistry, San Diego State University, CA 92182-1030, United States.
authors: Po-Shen
authors: PS
authors: Pan
authors: Robert C
authors: RC
authors: Vasko
authors: Stephanie A
authors: SA
authors: Lapera
authors: Victoria A
authors: VA
authors: Johnson
authors: Robert P
authors: RP
authors: Sellers
authors: Chun-Chieh
authors: CC
authors: Lin
authors: Chung-Mao
authors: CM
authors: Pan
authors: Melinda R
authors: MR
authors: Davis
authors: Veronica C
authors: VC
authors: Ardi
authors: Shelli R
authors: SR
authors: McAlpine
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D045744:Cell Line, Tumor; D047630:Depsipeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D015195:Drug Design; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D047630:Depsipeptides; C119376:sansalvamide A