Anti-HIV therapeutic agents

While over 33 million people are living with HIV/AIDS, the impact of HIV therapies has been shown by a nationwide decline in AIDS-related deaths. The vast majority of anti-HIV therapeutic agents have been limited to reverse transcriptase and protease inhibitors.5,6 However, the development of resistance to these inhibitors7 and the toxic side effects associated with these compounds8 indicate a major need for further discovery and development of alternative strategies such as those targeting other stages... 

CM with the Hindered Olefin 1,1-Disubstituted and trisub stituted olefins do not usually dimerize even in the presence of [Ru]-II, and these olefins are categorized as type Iff or type fV. The sterically crowded olefin such as 2-methyl-2-butene, however, was found to be available as a CM partner by Grubbs and co-workers. Porco and Qi employed this CM partner for the synthesis of clusianone 105, which is a potential anti-HIV therapeutic agent isolated from the floral resin of clusia species (Scheme 24.25). The isopropenyl moiety was smoothly incorporated into the side chain of clusianone precursor 104 by CM reaction of 102 with 103 as a solvent. 

Disubstituted alkenes do not usually dimerize in the presence of catalyst [Ruj-II but when isobutylene is used as solvent, a small amount of background dimerization is observed. Grubbs and coworkers reported the superior behavior of 2-methyl-2-butene for this kind of reactions [24], while Porco and Qi employed this reagent for the synthesis of clusianone, a potential anti-HIV therapeutic agent isolated from the floral resin of Clusia species [25]. The isoprenyl side chain was installed in good yield from 49 by allylic acetate reduction followed by CM in neat 2-methyl-2-butene in the presence of catalyst [Ru]-II. Compound 50 was isolated and then transformed into the target molecule by nucleophilic demethylation (Scheme 10.15). 

The rapid spread of acquired immune deficiency syndrome (AIDS) has prompted numerous efforts to develop therapeutic agents against the human immunodeficiency virus type 1 (HIV-1) [2351. Efforts have focused on inhibition of the virally encoded reverse transcriptase (RT) enzyme, which is responsible for the conversion of retroviral RNA to proviral DNA. The nucleoside RT inhibitors 3 -azidothymidine (AZT) and dideoxyinosine (ddl) have proven to be clinically useful anti HIV-1 agents [236], but due to their lack of selectivity versus other DNA polymerases, these compounds are flawed by their inherent toxi-... 

Therapeutic Function Antiviral, Anti-HIV virus agent... 

Wliich anti-HIV therapeutics specifically target the infecting agent ... 

The triterpene sapogenins betulinic acid, oleanolic acid and ursolic acid show cytotoxic and anti-inflammatory effects, and based on their structures novel chemopreventive and anticancer agents are being developed (Liby et al., 2007). A derivative of betulinic acid, beviri-mat, is the first member of a new class of anti HIV therapeutics, maturase inhibitors. These... 

Although the primary objective of any vaccine is its prophylactic use (i.e. prevention of future occurrence of a disease), AIDS vaccines may also be of therapeutic value. This supposition is based upon the fact that the immune system controls the viral infection for a time period. Hence, any agent capable of enhancing the anti-HIV immune response may prolong this elfect. 

Protease inhibitors are often incorporated into the comprehensive treatment of people with HIV infection. Use of these drugs in combination with other anti-HIV agents is discussed in more detail later in this chapter (see HIV and the Treatment of AIDS ). In addition, a specific protease inhibitor can be combined with a low dose of ritonavir—a process known as protease-inhibitor boosting. 34,69 Ritonavir inhibits the hepatic breakdown of the other (primary) protease drug, thereby enabling the primary drug to exert better therapeutic effects at a lower dose.34... 

The aromatic polycyclic diones hypericin and pseudohypericin, which are present in plants of the family Hypericum (St. John s wort), have been accredited with anti-HIV activity for more than a decade. They possess the capacity to inactivate HIV virions directly as well as to interfere with their assembly or processing. Hypericin has received continued interest as a potential therapeutic agent and was more recently found to interact with preintegration complexes (PICs) and thus affect the proviral DNA integration process (De Clercq, 2000). 

The dibenzylbutyrolactone lignan matairesinol was also found to be an anti-HIV agent [110], although the sample used in this bioassay was not isolated from a Taxus species. Another dibenzylbutyrolactone lignan, arctigenin, as well as its unsubstituted benzyl derivative exhibited anti-HIV replication activity, with EC50 values of 0.16 and 22 ig/mL and therapeutic index values of 5 and 9.1, respectively [111]. 

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