Ishaq KS, McLean JW, Morris-Natschke SL, Iyer N, Kucera LS; International Conference on AIDS.
Int Conf AIDS. 1996 Jul 7-12; 11: 71 (abstract no. Mo.A.1095).
Wake Forest University Medical Center, Winston-Salem, North Carolina, USA. Fax: 910-716-9928. E-mail: lkucera@bgsm.edu.
Objectives: The major objectives are to synthesize and evaluate membrane interactive cyclic phospholipid analogues and to conjugate them with AZT to enhance anti-HIV-1 selectivity. Methods: We have synthesized conformationally constrained phospholipid analogues with heteroalkyl chains and a phosphocholine moiety incorporated into cyclohexane rings. Biological evaluations were performed using 3H-TdR incorporation into total DNA to measure cytotoxicity and a syncytial plaque assay for anti-HIV-1 activity in CEM-SS cells. TC50 values for cytotoxicity and EC50 values for plaque inhibition were determined using a computer program. Results: The cis and trans isomers of 3-(hexadecylthio) cyclohexyl phosphocholine gave an TC50 of 15.7 and 11.5 micromolar, respectively, for cytotoxicity and EC50 of 0.36 and 0.84 micromolar, respectively, for anti-HIV-1 activity. Also, we synthesized the cyclopentane-AZT and cyclohexane-AZT conjugates. The cyclopentane-AZT conjugate had an TC50 of 29.8 micromolar for cytotoxicity and an EC50 of 0.05 micromolar for anti-HIV-1 activity. Experiments are in progress to evaluate the cyclohexane-AZT conjugate. Conclusions: The selectivity (TC50/EC50) of the cis isomer (44) was about three-fold better than the trans isomer (14) of the cyclohexyl phosphocholine. The cyclopentane-AZT conjugate had a selectivity of 596. Further modification of conformationally constrained phospholipids and their AZT conjugates are in progress to increase anti-HIV-1 selectivity.
Publication Types:
Keywords:
- HIV-1
- Phospholipids
- Phosphorylcholine
- Plaque Assay
- Zidovudine
- chemical synthesis
- methods
Other ID:
UI: 102217064
From Meeting Abstracts