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Design and synthesi...
Design and synthesis of HIV-1 protease inhibitors
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- Alterman, Mathias (författare)
- Uppsala universitet,Institutionen för farmaceutisk kemi
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(creator_code:org_t)
- ISBN 9155449069
- Uppsala : Acta Universitatis Upsaliensis, 2001
- Engelska 70 s.
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Serie: Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, 0282-7484 ; 245
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Abstract
Ämnesord
Stäng
- Human Immunodeficiency Virus (HIV) is the causative agent of Acquired Immune Deficiency Syndrome (AIDS). The C2-symmetric HIV-1 protease is one of the prime targets for chemotherapy in the treatment of the HIV infection. Inhibition of HIV-1 protease leads to immature and non-infectious viral particles. Design and synthesis of a number of C2-symmetrical C-terminal duplicated HIV-1 protease inhibitors and subsequent biological evaluation is presented in this thesis.A versatile three step synthetic route has been developed using a carbohydrate as an inexpensive chiral starting material thus allowing inhibitors with the desired stereochemistry to be obtained. By this efficient method a series of tailor-made P2/P2' modified inhibitors were synthesized, and these were evaluated on purified HIV-1 protease and in HIV-1 infected cell assays. Highly active HIV-1 protease inhibitors were identified among the tested compounds. Analyses of the X-ray crystal structures of two of the most active compounds, as complexes with the protease, guided the further design of P1/P1' elongated inhibitors. Substitutions in the para-position of the P1/P1' benzyl groups were promoted efficiently by microwave-irradiated of palladium-catalyzed reactions. Particular modifications in the P1/P1' region of the inhibitors resulted in a 40-fold increase of the anti-viral activity on HIV-1 infected cells. Furthermore, a fast, efficient, and general one-pot microwave enhanced synthesis protocol for transformations of organo-bromides to tetrazoles was developed and applied on the inhibitor scaffold. Attachment of linker molecules to the P1/P1' benzyl groups of one inhibitor was used to develop of sensitivity enhancer tools in surface plasmon resonance biosensor assays. These new assays enable the evaluation of low-molecular weight compounds as HIV-1 protease inhibitors.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medicinal Chemistry (hsv//eng)
Nyckelord
- Pharmaceutical chemistry
- HIV-1
- Protease
- Inhibitors
- Farmaceutisk kemi
- Pharmaceutical chemistry
- Farmaceutisk kemi
- Organic Pharmaceutical Chemistry
- organisk farmaceutisk kemi
Publikations- och innehållstyp
- vet (ämneskategori)
- dok (ämneskategori)
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