Synthesis and biological evaluation of santacruzamate A analogues for anti-proliferative and immunomodulatory activity |
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| Affiliation: | 1. Division of Medicinal Chemistry, Department of Pharmaceutical Sciences, University of Connecticut, 69 N. Eagleville Rd, Storrs, CT 06269, USA;2. Department of Molecular and Cell Biology, University of Connecticut, 91 N. Eagleville Rd, Storrs, CT 06269, USA;1. Department of Medicinal Chemistry, School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan;2. Department of Instrumental Analysis, School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan;1. Faculty of Chemistry, Adam Mickiewicz University, Umultowska 89b, 61614 Poznań, Poland;2. Institute of Bioorganic Chemistry, Polish Academy of Science, Noskowskiego 12/14, 61704 Poznań, Poland;1. Laboratoire de Synthèse Organique, CNRS, Ecole Polytechnique, ENSTA ParisTech-UMR 7652, Université Paris-Saclay, 828 Bd des Maréchaux, 91128 Palaiseau, France;2. Laboratoire de Chimie et d’Electrochimie, Département de Chimie, Université des sciences et de la technologie d''Oran. Mohamed Boudiaf USTO-MB, BP1505,El M''nouar 31000 Oran, Algeria;1. Department of Pharmaceutical Technology, Faculty of Pharmacy, Charles University in Prague, Heyrovského 1203, 50005 Hradec Králové, Czech Republic;2. Institute of Organic Chemistry and Technology, Faculty of Chemical Technology, University of Pardubice, Studentská 573, 53210 Pardubice, Czech Republic;3. Department of Inorganic and Organic Chemistry, Faculty of Pharmacy, Charles University in Prague, Heyrovského 1203, 50005 Hradec Králové, Czech Republic;4. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University in Prague, Heyrovského 1203, 50005 Hradec Králové, Czech Republic;5. Laboratory for Mycobacterial Diagnostics and Tuberculosis, Regional Institute of Public Health in Ostrava, Partyzánské náměstí 7, 70200 Ostrava, Czech Republic |
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| Abstract: | 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. |
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| Keywords: | Santacruzamate A Natural product analogues Enzyme assays Anti-proliferative activity Immune modulation |
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