203576-71-0Relevant academic research and scientific papers
Anti-AIDS agents - XXVII. Synthesis and anti-HIV activity of betulinic acid and dihydrobetulinic acid derivatives
Hashimoto, Fumio,Kashiwada, Yoshiki,Cosentino, L. Mark,Chen, Chin-Ho,Garrett, Patricia E.,Lee, Kuo-Hsiung
, p. 2133 - 2143 (1997)
Two series of lupane-type triterpenoic acid derivatives were synthesized and evaluated for their inhibitory activity against HIV-1 replication in acutely infected H9 cells, based on the fact that betulinic acid (1) and dihydrobetulinic acid (9) were identified as anti-HIV agents. Among the derivatives, 3-O-(3',3'-dimethylsuccinyl)-betulinic acid (3) and 3-O-(3',3'-dimethylsuccinyl)-dihydrobetulinic acid (11) both demonstrated extremely potent inhibitory activity with EC50 values of -4 μM, and remarkable in vitro therapeutic index (TI) values of 20,000 and 14,000, respectively. 3-O-(3',3'-dimethylglutaryl)-betulinic acid (4) and -dihydrobetulinic acid (12), 3-O-diglycolyl-betulinic acid (5) and -dihydrobetulinic acid (13) and 3-O-glutaryl-betulinic acid (6) were also potent inhibitors of HIV replication with EC50 values ranging from 0.04 to 2.3 x 10-3 μM and TI values from 292 to 2344. In addition, compounds 11 and 12 were also active against HIV replication in a monocyte cell line and in peripheral blood mononuclear cells. Our in vitro assay indicated that these compounds are not inhibitors of HIV-1 reverse transcriptase, whereas they inhibited syncytia formation completely in a concentration range of 20-40 μg/mL. However, 3-O-(2',2'-dimethylsuccinyl)-betulinic acid (2) was also found to be an inhibitor of HIV-induced membrane fusion with an IC100 value of 20 μg/mL, though it displayed significantly lower anti-HIV activity than foregoing compounds with an EC50 value of 2.7 μM and TI of 6.7. Further study is underway to determine the mechanisms of action of these compounds.
Preparation of betulinic acid derivatives by chemical and biotransformation methods and determination of cytotoxicity against selected cancer cell lines
Baratto, Leopoldo C.,Porsani, Mariana V.,Pimentel, Ida C.,Pereira Netto, Adaucto B.,Paschke, Reinhard,Oliveira, Brás H.
, p. 121 - 131 (2013)
Several novel 2,4-dinitrophenylhydrazone betulinic acid derivatives have been prepared by chemical and biotransformation methods using fungi and carrot cells. Some compounds showed significant cytotoxicity and selectivity against some tumor cell lines. The most active, 3-[(2,4-dinitrophenyl)hydrazono]lup- (20R)-29-oxolupan-28-oic acid, showed IC50 values between 1.76 and 2.51 μM against five human cancer cell lines. The most selective, 3-hydroxy-20-[(2,4-dinitrophenyl)hydrazono]-29-norlupan-28-oic acid, was five to seven times more selective for cancer cells when compared to fibroblasts. Cell cycle analysis and apoptosis induction were studied for the most active derivatives.
Design, Synthesis, and SAR of C-3 Benzoic Acid, C-17 Triterpenoid Derivatives. Identification of the HIV-1 Maturation Inhibitor 4-((1 R,3a S,5a R,5b R,7a R,11a S,11b R,13a R,13b R)-3a-((2-(1,1-Dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1 H-cyclopenta[ a]chrysen-9-yl)benzoic Acid (GSK3532795, BMS-955176)
Regueiro-Ren, Alicia,Swidorski, Jacob J.,Liu, Zheng,Chen, Yan,Sin, Ny,Sit, Sing-Yuen,Chen, Jie,Venables, Brian L.,Zhu, Juliang,Nowicka-Sans, Beata,Protack, Tricia,Lin, Zeyu,Terry, Brian,Samanta, Himadri,Zhang, Sharon,Li, Zhufang,Easter, John,Beno, Brett R.,Arora, Vinod,Huang, Xiaohua S.,Rahematpura, Sandhya,Parker, Dawn D.,Haskell, Roy,Santone, Kenneth S.,Cockett, Mark I.,Krystal, Mark,Meanwell, Nicholas A.,Jenkins, Susan,Hanumegowda, Umesh,Dicker, Ira B.
, p. 7289 - 7313 (2018/09/06)
GSK3532795, formerly known as BMS-955176 (1), is a potent, orally active, second-generation HIV-1 maturation inhibitor (MI) that advanced through phase IIb clinical trials. The careful design, selection, and evaluation of substituents appended to the C-3 and C-17 positions of the natural product betulinic acid (3) was critical in attaining a molecule with the desired virological and pharmacokinetic profile. Herein, we highlight the key insights made in the discovery program and detail the evolution of the structure-activity relationships (SARs) that led to the design of the specific C-17 amine moiety in 1. These modifications ultimately enabled the discovery of 1 as a second-generation MI that combines broad coverage of polymorphic viruses (EC50 15 nM toward a panel of common polymorphisms representative of 96.5% HIV-1 subtype B virus) with a favorable pharmacokinetic profile in preclinical species.
Synthetic Analogues of Betulinic Acid as Potent Inhibitors of PS1/BACE1 Interaction to Reduce Aβ Generation
Zhang, Chenlu,Wang, Xiaoyin,Cui, Jin,Li, Xiaohang,Zhang, Yangming,Wang, Xin,Gu, Haifeng,Li, Wei,Xie, Xin,Zhao, Jian,Pei, Gang,Nan, Fajun
, p. 103 - 112 (2017/02/05)
The lupane-type triterpenoids are endowed with a wide range of biological activities such as antiviral, anti-inflammatory and anticancer activity. We describe here its potential application in Alzheimer's disease (AD) treatment as an inhibitor of PS1/BACE1 interaction. 3-α-Akebonoic acid, which emanated from a high throughput screening (HTS), was discovered to interfere with PS1/BACE1 interaction and reduce amyloid β-protein (Aβ) production. In view of the limited source, we instead used naturally rich betulinic acid (compound 2) as starting material for lead optimization and a focused library of its derivatives was constructed to gain a better understanding of the structure activity relationship (SAR) of triterpenoid-type inhibitor of PS1/BACE1 interaction. Compound 22 was finally chosen as the most potent PS1/BACE1 interaction inhibitor, which reduced Aβ generation effectively.
NOVEL C28-ANALOGUES WITH C3-MODIFICATIONS OF TRITERPENE DERIVATIVES AS HIV INHIBITORS
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Page/Page column 57, (2017/03/08)
The present invention relates to compounds of novel C28-analogues with C3- modifications of triterpene derivatives of formula (I); or pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, tautomers, stereoisomers, prodrugs, compositions or combination thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, X, and Z are as defined herein. The present invention also relates to pharmaceutical compositions comprising compounds of formula (I) useful for the treatment of viral diseases and particularly HIV mediated diseases.
C-3 benzoic acid derivatives of C-3 deoxybetulinic acid and deoxybetulin as HIV-1 maturation inhibitors
Liu, Zheng,Swidorski, Jacob J.,Nowicka-Sans, Beata,Terry, Brian,Protack, Tricia,Lin, Zeyu,Samanta, Himadri,Zhang, Sharon,Li, Zhufang,Parker, Dawn D.,Rahematpura, Sandhya,Jenkins, Susan,Beno, Brett R.,Krystal, Mark,Meanwell, Nicholas A.,Dicker, Ira B.,Regueiro-Ren, Alicia
, p. 1757 - 1770 (2016/04/05)
A series of C-3 phenyl- and heterocycle-substituted derivatives of C-3 deoxybetulinic acid and C-3 deoxybetulin was designed and synthesized as HIV-1 maturation inhibitors (MIs) and evaluated for their antiviral activity and cytotoxicity in cell culture. A 4-subsituted benzoic acid moiety was identified as an advantageous replacement for the 3′3′-dimethylsuccinate moiety present in previously disclosed MIs that illuminates new aspects of the topography of the pharmacophore. The new analogs exhibit excellent in vitro antiviral activity against wild-type (wt) virus and a lower serum shift when compared with the prototypical HIV-1 MI bevirimat (1, BVM), the first MI to be evaluated in clinical studies. Compound 9a exhibits comparable cell culture potency toward wt virus as 1 (WT EC50 = 16 nM for 9a compared to 10 nM for 1). However, the potency of 9a is less affected by the presence of human serum, while the compound displays a similar pharmacokinetic profile in rats to 1. Hence 9a, the 4-benzoic acid derivative of deoxybetulinic acid, represents a new starting point from which to explore the design of a 2nd generation MI.
Discovery of BMS-955176, a Second Generation HIV-1 Maturation Inhibitor with Broad Spectrum Antiviral Activity
Regueiro-Ren, Alicia,Liu, Zheng,Chen, Yan,Sin, Ny,Sit, Sing-Yuen,Swidorski, Jacob J.,Chen, Jie,Venables, Brian L.,Zhu, Juliang,Nowicka-Sans, Beata,Protack, Tricia,Lin, Zeyu,Terry, Brian,Samanta, Himadri,Zhang, Sharon,Li, Zhufang,Beno, Brett R.,Huang, Xiaohua S.,Rahematpura, Sandhya,Parker, Dawn D.,Haskell, Roy,Jenkins, Susan,Santone, Kenneth S.,Cockett, Mark I.,Krystal, Mark,Meanwell, Nicholas A.,Hanumegowda, Umesh,Dicker, Ira B.
, p. 568 - 572 (2016/07/06)
HIV-1 maturation inhibition (MI) has been clinically validated as an approach to the control of HIV-1 infection. However, identifying an MI with both broad polymorphic spectrum coverage and good oral exposure has been challenging. Herein, we describe the design, synthesis, and preclinical characterization of a potent, orally active, second generation HIV-1 MI, BMS-955176 (2), which is currently in Phase IIb clinical trials as part of a combination antiretroviral regimen.
Heterocycle-fused lupane triterpenoids inhibit Leishmania donovani amastigotes
Haavikko, Raisa,Nasereddin, Abedelmajeed,Sacerdoti-Sierra, Nina,Kopelyanskiy, Dmitry,Alakurtti, Sami,Tikka, Mari,Jaffe, Charles L.,Yli-Kauhaluoma, Jari
supporting information, p. 445 - 451 (2014/04/17)
The synthesis of heterocyclic betulin derivatives and their activity against Leishmania donovani is reported. Betulonic acid was used as a versatile intermediate. Several different fused heterocycles were introduced at the 2,3-position of the lupane skeleton including isoxazole, pyrazine, pyridine, indole and pyrazole rings. Also the 28-position was modified. Three compounds, 5, 8 and 25, showed low micromolar activity with IC50 values of 13.2, 4.3 and 7.2 μM, respectively. Compound 8 showed the best activity and selectivity, and its activity was tested on infected macrophages using a concentration, 5 μM, where no macrophage toxicity was exhibited. Interestingly, the activity of compound 8 on axenic amastigotes and Leishmania-infected macrophages was similar.
C-17 BICYCLIC AMINES OF TRITERPENOIDS WITH HIV MATURATION INHIBITORY ACTIVITY
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, (2013/11/19)
Compounds having drug and bio-affecting properties, their pharmaceutical compositions and methods of use are set forth. In particular, C-17 bicyclic amines of triterpenoids that possess unique antiviral activity are provided as HIV maturation inhibitors, as represented by compounds of Formulas I, II and III: These compounds are useful for the treatment of HIV and AIDS.
C-17 AND C-3 MODIFIED TRITERPENOIDS WITH HIV MATURATION INHIBITORY ACTIVITY
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, (2012/08/27)
Compounds having drug and bio-affecting properties, their pharmaceutical compositions and methods of use are set forth. In particular, C-17 and C-3 modified triterpenoids that possess unique antiviral activity are provided as HIV maturation inhibitors, as represented by compounds of Formulas I, II and III. These compounds are useful for the treatment of HIV and AIDS.
