Synthesis and biological evaluation of santacruzamate A analogues for anti-proliferative and immunomodulatory activity

• Published in: Bioorganic & medicinal chemistry Vol. 24; no. 21; pp. 5183 - 5196
• Main Authors: Gromek, Samantha M., deMayo, James A., Maxwell, Andrew T., West, Ashley M., Pavlik, Christopher M., Zhao, Ziyan, Li, Jin, Wiemer, Andrew J., Zweifach, Adam, Balunas, Marcy J.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.11.2016; Elsevier
• Subjects: Anti-proliferative activity; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biochemistry & Molecular Biology; Carbamates - chemical synthesis; Carbamates - chemistry; Carbamates - pharmacology; Cell Proliferation - drug effects; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Enzyme assays; Humans; Immune modulation; Life Sciences & Biomedicine; MCF-7 Cells; Molecular Structure; Natural product analogues; Pharmacology & Pharmacy; Physical Sciences; Santacruzamate A; Science & Technology; Structure-Activity Relationship; T-Lymphocytes, Cytotoxic - drug effects; T-Lymphocytes, Cytotoxic - immunology; Santacruzamate A; Enzyme assays; Anti-proliferative activity; Natural product analogues; Immune modulation; HDAC INHIBITORS; CANCER-CELLS; TARGET; ACIDS; LARGAZOLE; HISTONE-DEACETYLASE INHIBITORS; CYANOBACTERIUM SYMPLOCA SP; POTENT; ANTAGONISTS; PROTEINS
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2016.08.040

[Display omitted] Santacruzamate A (SCA) is a natural product isolated from a Panamanian marine cyanobacterium, previously reported to have potent and selective histone deacetylase (HDAC) activity. To optimize the enzymatic and cellular activity, 40 SCA analogues were synthesized in a systematic exploration of the zinc-binding group (ZBG), cap terminus, and linker region. Two cap group analogues inhibited proliferation of MCF-7 breast cancer cells, with analogous increased degranulation of cytotoxic T cells (CTLs), while one cap group analogue reduced CTL degranulation, indicative of suppression of the immune response. Additional testing of these analogues resulted in reevaluation of the previously reported SCA mechanism of action. These analogues and the resulting structure–activity relationships will be of interest for future studies on cell proliferation and immune modulation.