Synthesis and anti-HIV activity of a bile acid analog of cosalane

Kannan, Arunachalam; Clercq, Erik De; Pannecouque, Christophe; Witvrouw, Myriam; Hartman, Tracy L.; Turpin, Jim A.; Buckheit, Robert W.; Cushman, Mary

doi:10.1016/s0040-4020(01)00955-3

Cited by 25 publications

(9 citation statements)

References 30 publications

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“…Transport of the conjugates was observed to be influenced by charge and hydrophobicity around the C 24 position of the sterol nucleus. Another hybrid molecule with anti-HIV activity, a cholic acid analog of cosalane (see Figure 7) was designed to target the ileal bile acid transporter and thus facilitate the poor oral absorption of cosalane, an anti-HIV agent [126]. The bile acid analog retained antiviral activity but was less potent than cosalane itself.…”

Section: Bile Acid-containing Prodrugsmentioning

confidence: 99%

“…This was believed to be, at least partially, due to decrease in lipophilicity of the steroidal moiety compared to the parent compound. Three hydroxyl groups, however, were believed to increase the affinity of the hybrid towards the transport system, which is why they were preserved in the molecule [126]. To investigate steroidal pyrazole templates as drug carriers, a series of novel C 2 -C 3 annulated bile acid pyrazoles were synthesized by Bhat et al [127,128].…”

Section: Bile Acid-containing Prodrugsmentioning

confidence: 99%

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Exploitation of Bile Acid Transport Systems in Prodrug Design

Sievänen

2007

Molecules

102

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Abstract:The enterohepatic circulation of bile acids is one of the most efficient recycling routes in the human body. It is a complex process involving numerous transport proteins, which serve to transport bile acids from the small intestine into portal circulation, from the portal circulation into the hepatocyte, from the hepatocyte into the bile, and from the gall bladder to the small intestine. The tremendous transport capacity and organ specificity of enterohepatic circulation combined with versatile derivatization possibilities, rigid steroidal backbone, enantiomeric purity, availability, and low cost have made bile acids attractive tools in designing pharmacological hybrid molecules and prodrugs with the view of improving intestinal absorption, increasing the metabolic stability of pharmaceuticals, specifically targeting drugs to organs involved in enterohepatic circulation, as well as sustaining therapeutically reasonable systemic concentrations of active agents. This article briefly describes bile acid transport proteins involved in enterohepatic circulation, summarizes the key factors affecting on the transport by these proteins, and reviews the use of bile acids and their derivatives in designing prodrugs capable of exploiting the bile acid transport system.

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Section: Bile Acid-containing Prodrugsmentioning

confidence: 99%

Section: Bile Acid-containing Prodrugsmentioning

confidence: 99%

Exploitation of Bile Acid Transport Systems in Prodrug Design

Sievänen

2007

Molecules

102

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“…The poor oral availability of cosalane is mainly attributed to its poor permeation across the intestinal epithelium due to its very high lipophilicity and membrane interacting nature. With the aim to retain the anti HIV activity and to enhance bioavailibility of cosalane, Cushman and his group has synthesized [164] cosalane-bile acid conjugate 161 (Fig. 44).…”

Section: Bile Acid Based Conjugatesmentioning

confidence: 99%

Steroidal Conjugates and Their Pharmacological Applications

Salunke

Hazra²,

Pore³

2006

CMC

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Nature continues to be the main source of inspiration for synthetic chemists in their quest to make novel conjugates, which can have different physical, biological and medicinal properties. Nature makes these conjugates from mixed biosynthesis and some of these chimeras are found to exhibit unusual biological properties. During the past two decades design of such entities has been receiving increasing attention. Among the hybrid natural products, hybrids of steroid frameworks have attracted great attention due to the significant biological properties and numerous therapeutic effects of steroids. The developments made over the past few years in the isolation, design and synthesis of steroidal conjugates and their pharmacological applications are discussed in this review.

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“…Dentre eles podemos citar o cosalano e seus análogos contendo vários grupos carboxilatos (Figura 13) 43 . Estes grupos hidrofílicos não penetram na membrana celular ou no envelope viral, impedindo assim a fusão do vírus com a célula (Figura 14) 44 .…”

Section: Bloqueando a Interação Da Gp 120 Com O Cd4unclassified

Drogas anti-VIH: passado, presente e perspectivas futuras

Souza

Almeida²

2003

Quím. Nova

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Recebido em 20/6/02; aceito em 22/10/02 DRUGS ANTI-HIV: PAST, PRESENT AND FUTURE PERSPECTIVES. Currently available anti-HIV drugs can be classified into three categories: nucleoside analogue reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs). In addition to the reverse transcriptase (RT) and protease reaction, various other events in the HIV replicative cycle can be considered as potential targets for chemotherapeutic intervention: (1) viral adsorption, through binding to the viral envelope glycoprotein gp120; (2) viral entry, through blockage of the viral coreceptors CXCR4 and CCR5; (3) virus-cell fusion, through binding to the viral envelope glycoprotein gp 41; (4) viral assembly and disassembly through NCp7 zinc finger-targeted agents; (5) proviral DNA integration, through integrase inhibitors and (6) INTRODUÇÃOOs vírus estão envolvidos em uma grande variedade de doenças crônicas e degenerativas, sendo responsáveis por mais de 60% das doenças causadas no homem 1 . A luta contra as infecções virais é difícil, pois a replicação viral é um processo intracelular, estando intimamente relacionada ao metabolismo das células infectadas. Um dos vírus mais estudados hoje em dia é o chamado vírus da imunodeficiência humana (VIH) ou "Human Immunodeficiency Ví-rus" (HIV) 2,3 , um vírus da família dos retrovírus (composto de ARN) 4 , capaz de parasitar o sistema imunológico do homem, levando a uma doença infecciosa conhecida como Síndrome da Imunodeficiência Adquirida (SIDA) ou "Acquired Immuno Deficiency Syndrome" (AIDS) 5,6 . O VIH é diferente dos outros vírus porque ataca e danifica o sistema imunológico, que é seu ponto principal de ataque no organismo humano. Um dos componentes do sistema imunológico são os linfócitos T, que atacam diretamente o microorganismo invasor. Dentre os linfócitos T existe uma classe denominada T4 (T CD4+ ou T-auxiliadores), que tem um papel de extrema importância no desencadear da resposta imunitária e na coordenação dessa mesma resposta, sendo o alvo principal do vírus VIH. Este vírus, ao infectar os linfócitos T CD4+, conduz à falta de coordenação do sistema imunológico e à sua progressiva inoperância, acabando por estabelecer uma imunodeficiência 7 . CICLO DA REPLICAÇÃO VIRALPara a obtenção de drogas eficazes no combate ao vírus VIH é extremamente importante conhecer como o vírus infecta o organismo (Figura 1) [8][9][10] . A infecção de uma célula ocorre quando o vírus VIH se liga a um receptor celular, geralmente o T CD4+, por meio de sua proteína gp 120; o vírus então se funde à membrana celular e o conteúdo da cápside é liberado no citoplasma celular. A enzima do VIH, transcriptase reversa, catalisa a produção de uma cópia de ADN a partir do ARN do vírus VIH. A cópia de ADN de dupla hélice é então transportada ao núcleo celular onde uma segunda enzima do VIH, a integrase, catalisa a incorporação do ADN viral ao material genético do hospedeiro. A expressão subseqüente dos genes virais resulta na transcrição d...

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Synthesis and anti-HIV activity of a bile acid analog of cosalane

Cited by 25 publications

References 30 publications

Exploitation of Bile Acid Transport Systems in Prodrug Design

Exploitation of Bile Acid Transport Systems in Prodrug Design

Steroidal Conjugates and Their Pharmacological Applications

Drogas anti-VIH: passado, presente e perspectivas futuras

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