期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 21, 期 7, 页码 1917-1921出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2011.02.070
关键词
Anti-HIV; Cellular uptake; 2 ',3 '-Didehydro-2 ',3 '-dideoxythymidine; Fatty acids; Stavudine
资金
- CONRAD [MSA-03-367]
- Eastern Virginia Medical School [HRN-A-00-98-00020-00]
- United States Agency for International Development (USAID)
- National Science Foundation [CHE 0748555]
- National Center for Research Resources, NIH
- [1 P20 RR16457]
A number of 5'-O-fatty acyl derivatives of 2',3'-didehydro-2',3'-dideoxythymidine (stavudine, d4T) were synthesized and evaluated for anti-HIV activities against cell-free and cell-associated virus, cellular cytotoxicity, and cellular uptake studies. The conjugates were found to be more potent than d4T. Among these conjugates, 5'-O-12-azidododecanoyl derivative of d4T (2), displaying EC50 = 3.1-22.4 mu M, showed 4- to 9-fold higher activities than d4T against cell-free and cell-associated virus. Cellular uptake studies were conducted on CCRF-CEM cell line using 5(6)-carboxyfluorescein derivatives of d4T attached through beta-alanine (9) or 12-aminododecanoic acid (10) as linkers. The fluorescein-substituted analog of d4T with long chain length (10) showed 12- to 15-fold higher cellular uptake profile than the corresponding analog with short chain length (9). These studies reveal that conjugation of fatty acids to d4T enhances the cellular uptake and anti-HIV activity of stavudine. (C) 2011 Elsevier Ltd. All rights reserved.
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