Synthesis of HIV-Maturation Inhibitor BMS-955176 from Betulin by an Enabling Oxidation Strategy

Ortiz, Adrian; Soumeillant, Maxime; Savage, Scott A.; Strotman, Neil A.; Haley, Matthew W.; Benkovics, Tamas; Nye, Jeffrey; Xu, Zhixing; Tan, Yee Sun; Ayers, Sloan; Gao, Qi; Kiau, Susanne

doi:10.1021/acs.joc.7b00438

Cited by 27 publications

(24 citation statements)

References 18 publications

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“…A concise and scalable synthesis of 64 starting from betulin in seven steps and 47% overall yield has been described. The synthesis is framed by an oxidation strategy highlighted by a CuI‐mediated aerobic oxidation of betulin, a highly selective PIF‐mediated dehydrogenation of an oxime, and a subsequent Lossen rearrangement, which occurs through a unique reaction mechanism for the installation of the C‐17 amino functionality 64 . Compound 64 demonstrated better anti‐HIV potency than BVM with no significant safety issues in its Phase IIa studies.…”

Section: Pentacyclic Triterpenoidmentioning

confidence: 99%

“…The rational design of substituents linked to the C-3 and C-28 positions of betulinic acid and analogs is critical in attaining new derivatives with improved anti-HIV activity. Although the development of BVMas the first-in-class HIV-1 maturation inhibitor was halted due to the high baseline drug resistance of HIV-1 variants with polymorphism, further studies identified the second-generation maturation BMS-955176(64), which showed significantly improved anti-HIV activity toward BVM-resistant variants. Unfortunately, the development of BMS-955176 was also discontinued by the pharmaceutical company GSK for gastrointestinal intolerance and treatment-emergent drug resistance by patients.…”

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confidence: 99%

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Recent advances in natural anti‐HIV triterpenoids and analogs

Morris‐Natschke

et al. 2020

Medicinal Research Reviews

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The human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) epidemic is one of the world's most serious health challenges. Although combination antiretroviral therapy provides effective viral suppression, current medicines used against HIV cannot completely eradicate the infectious disease and often have associated toxicities and severe side effects in addition to causing drug resistance. Therefore, the continued development of new antiviral agents with diverse structures and novel mechanisms of action remains a vital need for the management of HIV/AIDS. Natural products are an important source of drug discovery, and certain triterpenes and their analogs have demonstrated potential as pharmaceutical precursors for the treatment of HIV. Over the past decade, natural triterpenoids and analogs have been extensively studied to find new anti-HIV drugs. This review discusses

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Section: Pentacyclic Triterpenoidmentioning

confidence: 99%

mentioning

confidence: 99%

Recent advances in natural anti‐HIV triterpenoids and analogs

Morris‐Natschke

et al. 2020

Medicinal Research Reviews

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“…A concise and scalable second-generation synthesis of HIV maturation inhibitor 64 (Scheme 9) was published in 2017 [66]. The synthesis was based on an oxidation strategy involving a CuI mediated aerobic oxidation of betulin ( 2 ), a highly selective PIFA mediated dehydrogenation of an oxime, and a subsequent Lossen rearrangement, which occurred through a unique reaction mechanism for the installation of the C17 amino functionality.…”

Section: Derivatives Of Betulinic Acid Their Pharmacological Effementioning

confidence: 99%

“…The synthesis was based on an oxidation strategy involving a CuI mediated aerobic oxidation of betulin ( 2 ), a highly selective PIFA mediated dehydrogenation of an oxime, and a subsequent Lossen rearrangement, which occurred through a unique reaction mechanism for the installation of the C17 amino functionality. The synthetic procedure consisted of seven steps with a 47% overall yield and it begins from the abundant and inexpensive natural product betulin ( 2 ) (Scheme 9) [66]. The target compound 64 became a potent HIV-1 inhibitor in cell culture that exhibited a broad spectrum of antiviral effects that encompass the V370A- and ΔV370-containing polymorphic viruses.…”

Section: Derivatives Of Betulinic Acid Their Pharmacological Effementioning

confidence: 99%

Recent Achievements in Medicinal and Supramolecular Chemistry of Betulinic Acid and Its Derivatives ‡

2019

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The subject of this review article refers to the recent achievements in the investigation of pharmacological activity and supramolecular characteristics of betulinic acid and its diverse derivatives, with special focus on their cytotoxic effect, antitumor activity, and antiviral effect, and mostly covers a period 2015–2018. Literature sources published earlier are referred to in required coherences or from historical points of view. Relationships between pharmacological activity and supramolecular characteristics are included if such investigation has been done in the original literature sources. A wide practical applicability of betulinic acid and its derivatives demonstrated in the literature sources is also included in this review article. Several literature sources also focused on in silico calculation of physicochemical and ADME parameters of the developed compounds, and on a comparison between the experimental and calculated data.

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“…Betulinic acid (BA) as shown in Figure 1 and its derivatives, has been known as a potent group to inhibit HIV-protease (Aiken and Chen, 2005). Modification to enhance BA derivatives' protease inhibition were conducted by some previous studies (Kashiwada et al, 1996;Zhao et al, 2012;Ortiz et al, 2017;Huang et al, 2018). The changes of substituent on the C-28 position have been recognized to give different HIVprotease inhibition.…”

Section: Introductionmentioning

confidence: 99%

QSAR-Based Design of The More Potent Betulinic Acid Derivatives as HIV Maturation Inhibitor

Arief¹,

Pranowo²,

Mudasir³

et al. 2020

CMUJNS

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In this study, we make QSAR models from 29 of BA derivatives’ HIV maturation inhibition activities against their 3D descriptors. The best model involve 5 descriptors as follows: 1/log EC50 = -462.275 + (69.213 × TDB6u) + (723.745 × TDB6e) + (-0.576 × FPSA-3) + (0.849 × RDF140u) + (0.302 × RDF80e) r2 training = 0.7918; Q2 test = 0.9644; r2test = 0.9798; and r2m-test = 0.9445 TDB6u and TDB6e are the 3d topological distance-based autocorrelation-lag 6 /unweighted and weighted by Sanderson electronegati-vities, respectively. FPSA-3 is the value of charge weighted partial positive surface area / total molecular surface area. RDF140u is radial distribution function-140 / unweighted. RDF80e is radial distribution function-080/weighted by relative Sanderson electronegativities. The QSAR model was then used to design and predict some of the new BA derivatives’ HIV maturation activities. The best predicted compound had pEC50 value of -0.838 and EC50 value of 0.064 nM with the chemical IUPAC name of 4‐[(1R, 3aR, 5aR, 5bR, 7aS, 11aR, 11bS, 13aS,13bS)‐5a, 5b, 8, 8, 11b pentamethyl‐1‐(prop‐1‐en‐2‐yl)‐3a[({2‐[4‐(pyrimidin2yl)piperazin-1-yl]ethyl}amino) methyl]‐icosahydro‐1H-cyclopenta[a]chrysen‐9‐yl]benzoic acid. We also suggest the synthetic route to the proposed compound.

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Synthesis of HIV-Maturation Inhibitor BMS-955176 from Betulin by an Enabling Oxidation Strategy

Cited by 27 publications

References 18 publications

Recent advances in natural anti‐HIV triterpenoids and analogs

Recent advances in natural anti‐HIV triterpenoids and analogs

Recent Achievements in Medicinal and Supramolecular Chemistry of Betulinic Acid and Its Derivatives ‡

QSAR-Based Design of The More Potent Betulinic Acid Derivatives as HIV Maturation Inhibitor

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