Article

 

Structure–activity of Sansalvamide A Derivatives and their Apoptotic Activity in the Pancreatic Cancer Cell Line PL–45

 

Rodrigo A. Rodríguez, Po–Shen Pan, Robert C. Vasko, Chung–Mao Pan, William S. Disman, Shelli R. McAlpine^*

 

Department of Chemistry and Biochemistry, San Diego State University, 5500 Campanile Drive, San Diego, CA 92182–1030. ^*Responsible author

 

Recibido el 1 de mayo de 2008
Aceptado el 7 de julio de 2008

 

Abstract

We report the structure–activity relationship (SAR) of forty Sansalvamide A (San A) derivatives against human pancreatic ductal adenicarcinoma cell line PL–45. Our comprehensive evaluation of these compounds utilizes: cytotoxicity based SAR, molecular modeling, and ApoAlert Annexin V apoptosis detection to evaluate these potent compounds. Compared to current pancreatic cancer drugs, these San A analogs are structurally unique, and are potentially cytotoxic. Our comprehensive studies including molecular modeling show that a single N–methyl, a single D–amino acid (D–aa) or a single N –methyl D–aa appears to be critical for presenting the active conformation of San A peptide derivates to its biological target, and show that the San A peptide derivative 8 has the ability to selectively induce apoptosis. Thus, showing that this class of compounds are promising chemotherapeutic agents that will eliminate cells in an orderly manner without eliciting an undesired immune response.

Key words: structure–activity relationship, Sansalvamide A, human pancreatic adenicarcinoma, molecular modeling, apoptosis.

 

Resumen

Se describe la relación estructura–actividad (REA) de cuarenta derivados de Sansalvamida A (San A) frente a la línea celular PL–45 de adenocarcinoma ductal de páncreas humano. Para la evaluación de estos compuestos se hizo uso de: determinación de la citotoxicidad basada en REA, modelado molecular y detección de apoptosis ApoAlert Annexina V. Comparados a los medicamentos actualmente en uso contra cáncer pancreático, estos análogos de San A de estructura novedosa presentaron actividad citotóxica importante. Nuestros estudios que incluyen modelado molecular muestran que ya sea un solo grupo N–metilo, o un D–aminoácido (D–aa) o un N–metil D–aa pueden ser críticos para presentar la conformación activa del derivado peptídico de San A en su blanco biológico; además muestran que el derivado 8 tiene la habilidad de inducir selectivamente apoptosis. De esta forma, se muestra que esta clase de compuestos son agentes quimioterapéuticos prometedores que eliminan células de manera ordenada, sin presentar una respuesta inmune indeseable.

Palabras clave: relación estructura–actividad, Sansalvamida A, adenocarcinoma de páncreas humano, modelado molecular, apoptosis.

 

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Acknowledgements

We thank San Diego State University for financial support. We thank the Howell Foundation for support of R.A.R and R.C.V. We thank NIH (T90DK07015) for support of W.S.D. We thank the MHIRT program for their support of R.A.R.

 

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