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Synthesis and Structure-Activity Relationship of Norcantharidin Analogues as a Novel Class of Anti-HIV Agents

Author: ChenKeLiang
Tutor: SongDanQing
School: Peking Union Medical College , China
Course: Microbial and Biochemical Pharmacy
Keywords: Demethylated cantharidin Anti-HIV activity Structure-Activity Relationship
CLC: R96
Type: Master's thesis
Year: 2009
Downloads: 24
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Abstract


I Institute found that for the first time , the anti-HIV activity demethylated cantharidin (norcantharidin, NCTD, see Figure 1 ) , HIV-infected MT -4 , CEM , and H9/HIV-1IIIB three different lymphocyte passage cells Department able to show a good inhibitory activity , and lower the toxicity of the cells themselves , shows a higher selectivity index (SI). In addition , NCTD virus reverse transcriptase , protease and integrase enzyme showed no activity , suggesting that its mechanism of action and clinical use of anti-HIV drugs . NCTD also has a simple molecular structure , and therefore is an ideal anti-HIV lead compounds , structural modification and optimization , it is possible to obtain high activity and low toxicity , a novel mechanism of action of new anti-HIV drug candidates . In order to investigate the NCTD derivatives structure-activity relationship of anti-HIV activity , looking for activity necessary group obtained a more excellent activity and reduce the toxicity of analogs of this thesis to NCTD lead compound , while maintaining its bicyclic [2.2.1] heptane alkyl on the basis of the present structure skeleton , respectively, for its the five yuan anhydride ring and ring substituents on the structural modification designed and synthesized a 14 NCTD derivative , anti - HIV-1 activity by measuring the part of the target compound , preliminary summary of such the derivatives corresponding QSAR follows : (1) a saturated six-membered carbocyclic ring structure was activated essential . Introducing a double bond in the six-membered carbocyclic ring of 8,9 to change the degree of unsaturation of the compound , the activity is decreased , and the toxicity is also reduced at the same time ; (2) 7 - position is substituted by a hydrogen atom when the best activity . 7 - position of the introduction of substituents , decreased activity and the toxicity is also reduced at the same time ; (3 ) a five- anhydride ring is opened with increasing chain length of the monoester group , the decline of activity have different degrees of toxicity is also decreased . Wherein the SI value of the methyl ester derivative 4b NCTD considerable . This thesis measured all target compounds against herpes virus type 1 ( HSV - 1 ) activity , the results show that all NCTD derivatives are not anti - HSV-1 activity . This thesis designed and synthesized the 14 NCTD derivative , and its structure was confirmed by MS and ~ 1H NMR spectra is correct . Preliminary summary of such derivatives anti- HIV-1 structure-activity relationships , and laid the foundation for the further study of such compounds , the research have been published in Chinese core journals \

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