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Synthesis and Biological Evaluation of Macrocyclized Betulin Derivatives as a Novel Class of Anti-HIV-1 Maturation Inhibitors.

Tang J, Jones SA, Jeffery JL, Miranda SR, Galardi CM, Irlbeck DM, Brown KW, McDanal CB, Han N, Gao D, Wu Y, Shen B, Liu C, Xi C, Yang H, Li R, Yu Y, Sun Y, Jin Z, Wang E, Johns BA - Open Med Chem J (2014)

Bottom Line: A macrocycle provides diverse functionality and stereochemical complexity in a conformationally preorganized ring structure, and it occupies a unique chemical space in drug discovery.In this study, efficient synthetic routes to macrocyclized betulin derivatives have been established.The synthesis and biological evaluation of this novel series of HIV-1 maturation inhibitors will be discussed.

View Article: PubMed Central - PubMed

Affiliation: GlaxoSmithKline Research & Development, Research Triangle Park, NC 27709, USA.

ABSTRACT
A macrocycle provides diverse functionality and stereochemical complexity in a conformationally preorganized ring structure, and it occupies a unique chemical space in drug discovery. However, the synthetic challenge to access this structural class is high and hinders the exploration of macrocycles. In this study, efficient synthetic routes to macrocyclized betulin derivatives have been established. The macrocycle containing compounds showed equal potency compared to bevirimat in multiple HIV-1 antiviral assays. The synthesis and biological evaluation of this novel series of HIV-1 maturation inhibitors will be discussed.

No MeSH data available.


Synthesis of compounds 20k, 20l.
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S4: Synthesis of compounds 20k, 20l.

Mentions: Olefin metathesis was used as a final assembling strategy (Scheme 4). Allyl bromide was employed to make an extension at the C-30 position of compound 3. The resulting compound 16 was converted to compound 17 through similar approaches as described earlier. Subsequently, the carboxylic acid at the C-28 position was amidated with 6-hepten-1-amine to give compound 18, which was macrocyclized via olefin metathesis using Zhan 1B. During this process, the E/Z ratio of the newly formed double bond in compound 19 was not determined. Compound 20k was fully elaborated via similar steps as described earlier. The further reduction of the compound 20k using H2/Pd(OH)2 was unsuccessfully resulting in the ring opened product 20l in quantitative yield.


Synthesis and Biological Evaluation of Macrocyclized Betulin Derivatives as a Novel Class of Anti-HIV-1 Maturation Inhibitors.

Tang J, Jones SA, Jeffery JL, Miranda SR, Galardi CM, Irlbeck DM, Brown KW, McDanal CB, Han N, Gao D, Wu Y, Shen B, Liu C, Xi C, Yang H, Li R, Yu Y, Sun Y, Jin Z, Wang E, Johns BA - Open Med Chem J (2014)

Synthesis of compounds 20k, 20l.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4157350&req=5

S4: Synthesis of compounds 20k, 20l.
Mentions: Olefin metathesis was used as a final assembling strategy (Scheme 4). Allyl bromide was employed to make an extension at the C-30 position of compound 3. The resulting compound 16 was converted to compound 17 through similar approaches as described earlier. Subsequently, the carboxylic acid at the C-28 position was amidated with 6-hepten-1-amine to give compound 18, which was macrocyclized via olefin metathesis using Zhan 1B. During this process, the E/Z ratio of the newly formed double bond in compound 19 was not determined. Compound 20k was fully elaborated via similar steps as described earlier. The further reduction of the compound 20k using H2/Pd(OH)2 was unsuccessfully resulting in the ring opened product 20l in quantitative yield.

Bottom Line: A macrocycle provides diverse functionality and stereochemical complexity in a conformationally preorganized ring structure, and it occupies a unique chemical space in drug discovery.In this study, efficient synthetic routes to macrocyclized betulin derivatives have been established.The synthesis and biological evaluation of this novel series of HIV-1 maturation inhibitors will be discussed.

View Article: PubMed Central - PubMed

Affiliation: GlaxoSmithKline Research & Development, Research Triangle Park, NC 27709, USA.

ABSTRACT
A macrocycle provides diverse functionality and stereochemical complexity in a conformationally preorganized ring structure, and it occupies a unique chemical space in drug discovery. However, the synthetic challenge to access this structural class is high and hinders the exploration of macrocycles. In this study, efficient synthetic routes to macrocyclized betulin derivatives have been established. The macrocycle containing compounds showed equal potency compared to bevirimat in multiple HIV-1 antiviral assays. The synthesis and biological evaluation of this novel series of HIV-1 maturation inhibitors will be discussed.

No MeSH data available.