Design, Synthesis, Potency, and Cytoselectivity of Anticancer Agents Derived by Parallel Synthesis from -Aminosuberic Acid

详细信息    查看全文

• 作者：Pia Kahnberg ; Andrew J. Lucke ; Matthew P. Glenn ; Glen M. Boyle ; Joel D. A. Tyndall ; Peter G. Parsons ; David P. Fairlie
• 刊名：Journal of Medicinal Chemistry
• 出版年：2006
• 出版时间：December 28, 2006
• 年：2006
• 卷：49
• 期：26
• 页码：7611 - 7622
• 全文大小：544K
• 年卷期：v.49,no.26(December 28, 2006)
• ISSN：1520-4804

文摘

Chemotherapy in the last century was characterized by cytotoxic drugs that did not discriminate betweencancerous and normal cell types and were consequently accompanied by toxic side effects that were oftendose limiting. The ability of differentiating agents to selectively kill cancer cells or transform them to anonproliferating or normal phenotype could lead to cell- and tissue-specific drugs without the side effectsof current cancer chemotherapeutics. This may be possible for a new generation of histone deacetylaseinhibitors derived from amino acids. Structure-activity relationships are now reported for 43 compoundsderived from 2-aminosuberic acid that kill a range of cancer cells, 26 being potent cytotoxins against MM96Lmelanoma cells (IC₅₀ 20 nM-1 mages/entities/mgr.gif">M), while 17 were between 5- and 60-fold more selective in killing MM96Lmelanoma cells versus normal (neonatal foreskin fibroblasts, NFF) cells. This represents a 10- to 100-foldincrease in potency and up to a 10-fold higher selectivity over previously reported compounds derived fromcysteine (J. Med. Chem. 2004, 47, 2984). Selectivity is also an underestimate, because the normal cells,NFF, are rarely all killed by the drugs that also induce selective blockade of the cell cycle for normal butnot cancer cells. Selected compounds were tested against a panel of human cancer cell lines (melanomas,prostate, breast, ovarian, cervical, lung, and colon) and found to be both selective and potent cytotoxins(IC₅₀ 20 nM-1 mages/entities/mgr.gif">M). Compounds in this class typically inhibit human histone deacetylases, as evidencedby hyperacetylation of histones in both normal and cancer cells, induce expression of p21, and differentiatesurviving cancer cells to a nonproliferating phenotype. These compounds may be valuable leads for thedevelopment of new chemotherapeutic agents.