sansalvamide-a and Colonic-Neoplasms

We report an extensive structure-activity relationship (SAR) of 62 compounds active against two drug-resistant colon cancer cell lines. Our comprehensive evaluation of two generations of compounds utilizes SAR, NMR, and molecular modeling to evaluate the key 3D features of potent compounds. Of the seven most potent compounds reported here, five are second-generation, emphasizing our ability to incorporate potent features found in the first generation and utilize their structures to design potency into the second generation. These analogs share no structural homology to current colon cancer drugs, are cytotoxic at levels on par with existing drugs treating other cancers, and demonstrate selectivity for drug-resistant colon cancer cell lines over noncancerous cell lines. Thus, we have established sansalvamide A as an excellent lead for treating multiple drug-resistant colon cancers.

Topics: Antineoplastic Agents; Cell Line, Tumor; Colonic Neoplasms; Depsipeptides; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Humans; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Structure; Structure-Activity Relationship

We have identified five derivatives of the natural product sansalvamide A that are potent against multiple drug-resistant colon cancer cell lines. These analogs share no structural homology to current colon cancer drugs, are cytotoxic at levels on par with existing drugs treating other cancers, and demonstrate selectivity for drug-resistant colon cancer cell lines over noncancerous cell lines. Thus, we have established sansalvamide A as a privileged structure for treating multiple drug-resistant colon cancers.

Topics: Antineoplastic Agents; Cell Line, Tumor; Colonic Neoplasms; Depsipeptides; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Humans; Structure-Activity Relationship

Synthesis of twelve Sansalvamide A derivatives and their SAR against colon cancer (HT-29).

Topics: Amino Acids; Cell Line, Tumor; Cell Proliferation; Colonic Neoplasms; Depsipeptides; Humans; Molecular Structure; Structure-Activity Relationship

We report the synthesis of thirty-six Sansalvamide A derivatives, and their biological activity against colon cancer HT-29 cell line, a microsatellite stable (MSS) colon cancer cell-line. The thirty-six compounds can be divided into three subsets, where the first subset of compounds contains L-amino acids, the second subset contains D-amino acids, and the third subset contains both D- and L-amino acids. Five compounds exhibited excellent inhibitory activity (>75% inhibition). The structure-activity relationship (SAR) of the compounds established that a single D-amino acid in position 2 or 3 gave up to a 10-fold improved cytotoxicity over Sansalvamide A peptide. This work highlights the importance of residues 2 and 3 and the role of D-amino acids in the extraordinary SAR for this compound class.

Topics: Amino Acids; Antineoplastic Agents; Colonic Neoplasms; Depsipeptides; HT29 Cells; Humans; Inhibitory Concentration 50; Structure-Activity Relationship; Thymidine; Tumor Cells, Cultured