- Synthesis of Conjugates of Lupane-Type Pentacyclic Triterpenoids with 2-Aminoethane- and N-Methyl-2-Aminoethanesulfonic Acids. Assessment of in vitro Toxicity
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Conjugates of betulin and betulinic and betulonic acids with 2-aminoethane- and N-methyl-2-aminoethanesulfonic acids were synthesized for the first time and were interesting as potential biologically active compounds. Experiments in vitro in MDCK cell culture using the MTT assay found that betulin and betulinic-acid derivatives with aminoethanesulfonic acid bound to triterpene C-3 or C-28 through an ester linker were less toxic than the native compounds.
- Komissarova,Dubovitskii,Shitikova,Vyrypaev,Spirikhin,Eropkina,Lobova,Eropkin, M. Yu.,Yunusov
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- Synthetic Analogues of Betulinic Acid as Potent Inhibitors of PS1/BACE1 Interaction to Reduce Aβ Generation
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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.
- Zhang, Chenlu,Wang, Xiaoyin,Cui, Jin,Li, Xiaohang,Zhang, Yangming,Wang, Xin,Gu, Haifeng,Li, Wei,Xie, Xin,Zhao, Jian,Pei, Gang,Nan, Fajun
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- Synthesis and pharmacological effects of diosgenin—Betulinic acid conjugates
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The target diosgenin–betulinic acid conjugates are reported to investigate their ability to enhance and modify the pharmacological effects of their components. The detailed synthetic procedure that includes copper(I)-catalyzed Huisgen 1,3-dipolar cycloaddition (click reaction), and palladium-catalyzed debenzylation by hydrogenolysis is described together with the results of cytotoxicity screening tests. Palladium-catalyzed debenzylation reaction of benzyl ester intermediates was the key step in this synthetic procedure due to the simultaneous presence of a 1,4-disubstituted 1,2,3-triazole ring in the molecule that was a competing coordination site for the palladium catalyst. High pressure (130 kPa) palladium-catalyzed procedure represented a successful synthetic step yielding the required products. The conjugate 7 showed selective cytotoxicity in human T-lymphoblastic leukemia (CEM) cancer cells (IC50 = 6.5 ± 1.1 μM), in contrast to the conjugate 8 showing no cytotoxicity, and diosgenin (1), an adaptogen, for which a potential to be active on central nervous system was calculated in silico. In addition, 5 showed medium multifarious cytotoxicity in human T-lymphoblastic leukemia (CEM), human cervical cancer (HeLa), and human colon cancer (HCT 116). Betulinic acid (2) and the intermediates 3 and 4 showed no cytotoxicity in the tested cancer cell lines. The experimental data obtained are supplemented by and compared with the in silico calculated physico-chemical and absorption, distribution, metabolism, and excretion (ADME) parameters of these compounds.
- ?zdemir, Zülal,?aman, David,Rárová, Lucie,Rybková, Michaela,Vlk, Martin,Wimmer, Zdeněk
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- Betulinic acid: Isolation from Triphyophyllum peltatum and Ancistrocladus heyneanus, antimalarial activity, and crystal structure of the benzyl ester
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The known lupane-type triterpene betulinic acid (3) was isolated for the first time from Triphyophyllum peltatum and Ancistrocladus heyneanus. It was found to exhibit moderate to good in vitro antimalarial activity against asexual erythrocytic stages of t
- Bringmann, Gerhard,Saeb, Wael,Assi, Laurent Ake,Francois, Guido,Sankara Narayanan,Peters, Karl,Peters, Eva-Maria
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- Synthesis, characterization and cytotoxic activity of betulinic acid and Sec -betulinic acid derivatives against human colorectal carcinoma
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Different derivatives based on the betulinic acid triterpenoidal scaffold were synthesized and characterized spectroscopically. The derivatives including synthetic intermediates were evaluated for their cytotoxic activity against the human colorectal carc
- Ali, Mohd Tajudin Mohd,Zahari, Habsah,Aliasak, Aisyah,Lim, Siong Meng,Ramasamy, Kalavathy,Macabeo, Allan Patrick G.
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- Antimicrobial properties of amine- and guanidine-functionalized derivatives of betulinic, ursolic and oleanolic acids: Synthesis and structure/activity evaluation
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A series of 34 new amine- and guanidine-functionalized derivatives of betulinic, ursolic, and oleanolic acids were synthesized and tested for their antimicrobial activity against the growth of four bacterial strains (Escherichia coli, Acinetobacter baumannii, Pseudomonas aeruginosa, and Staphylococcus aureus (MRSA)) and two fungal strains (Candida albicans and Cryptococcus neoformans). The obtained compounds were also tested for the cytotoxic effect against HEK293 human embryonic kidney cell line and hemolytic activity against human red blood cells. Most of the prepared amino and guanidinium derivatives of betulinic, ursolic, and oleanolic acids showed a considerably higher bacteriostatic activity against methicillin-resistant S. aureus than the parent compounds. The most active compounds (MICs ≤ 0.25 μg/ml or 0.4–0.5 μM) were superior over the clinically used antibiotic vancomycin in the antibacterial effect (MIC of 1 μg/ml or 0.7 μM). Apart from antibacterial activity, new triterpene acid derivatives exhibited excellent antifungal activity against Cryptococcus neoformans, with MICs values being as low as 0.25 μg/ml (0.4 μM), and were approximately 65 times as active as fluconazole, a known antifungal agent. Four most promising compounds we identified (7, 13, 24, and 33) showed not only high bacteriostatic effect, but also low cytotoxicity against mammalian HEK293 cells and high hemolytic selectivity.
- Spivak, Anna Yu.,Khalitova, Rezeda R.,Nedopekina, Darya A.,Gubaidullin, Rinat R.
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- Betulinic acid-nitrogen heterocyclic derivatives: Design, synthesis, and antitumor evaluation in vitro
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Betulinic acid (BA) is a star member of the pentacyclic triterpenoid family, which exhibits great prospects for antitumor drug development. In an attempt to develop novel antitumor candidates, 21 BA-nitrogen heterocyclic derivatives were synthetized, in a
- Chen, Hongshan,Dai, Ziqi,Gao, Feng,Gu, Yuhao,Han, Nana,Huo, Su,Lei, Haimin,Li, Wen,Liu, Xiaojing,Qi, Jinchai,Tian, Xuehao,Wang, Penglong,Wu, Qianwen,Xie, Tianxin,Yang, Yuqin
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- Design, synthesis and biological evaluation of pentacyclic triterpene derivatives: Optimization of anti-Abl kinase activity
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Imatinib, an Abelson (ABL) tyrosine kinase inhibitor, is a lead molecular-targeted drug against chronic myelogenous leukemia (CML). To overcome its resistance and adverse effects, new inhibitors of ABL kinase are needed. Our previous study showed that the
- Ciftci, Halil I.,Radwan, Mohamed O.,Ozturk, Safiye E.,Gokce Ulusoy,Sozer, Ece,Ellakwa, Doha E.,Ocak, Zeynep,Can, Mustafa,Ali, Taha F.S.,Abd-Alla, Howaida I.,Yayli, Nurettin,Tateishi, Hiroshi,Otsuka, Masami,Fujita, Mikako
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- Targeting mitochondria: Esters of rhodamine B with triterpenoids are mitocanic triggers of apoptosis
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Triterpenoic acids, ursolic acid (1), oleanolic acid (2), glycyrrhetinic acid (3) and betulinic acid (4) were converted into their corresponding methyl 5–8 and benzyl esters 9–12 or benzyl amides 21–24. These derivatives served as starting materials for the synthesis of pink colored rhodamine B derivatives 25–36 which were screened for cytotoxicity in colorimetric SRB assays. All of the compounds were cytotoxic for a variety of human tumor cell lines. The activity of the benzyl ester derivatives 29–32 was lower than the cytotoxicity of the methyl esters 25–28. The benzyl amides 33–36 were the most cytotoxic compounds of this series. The most potential compound was a glycyrrhetinic acid rhodamine B benzyl amide 35. This compound showed activity against the different cancer cell lines in a two-digit to low three-digit nano-molar range. Staining experiments combined with fluorescence microscopy showed that this compound triggered apoptosis in A2780 ovarian carcinoma cells and acted as a mitocan.
- Wolfram, Ratna Kancana,Heller, Lucie,Csuk, René
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supporting information
p. 21 - 30
(2018/04/26)
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- Spectral and microscopic study of self-assembly of novel cationic spermine amides of betulinic acid
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Supramolecular characteristics of two spermine amides of betulinic acid (1 and 2) were studied by measuring and evaluating their UV–VIS-NIR spectra in aqueous acetonitrile and DOSY-NMR spectra in tetradeuteromethanol, accompanied by atomic force microscopy (AFM) images, scanning electron microscopy (SEM) micrographs, and transmission electron microscopy (TEM) micrographs. Fibrous supramolecular self-assembly of 1 and 2 was observed by AFM images, as well as by the SEM and TEM micrographs. Bathochromic shifts of the absorbance maximum at 870?nm to 1015–970?nm in the UV–VIS-NIR spectra were observed with increasing water content in the acetonitrile/water systems, indicating formation of fibrous J-type aggregates. Variable temperature DOSY-NMR spectral measurement showed non-linear dependence that also suggests self-assembly behavior of the studied systems. Chiral supramolecular structures were formed by self-assembling due to the chirality of the monomeric molecules. Application of aqueous media during self-assembly procedures is an important factor in the development of targeted drug delivery systems.
- Bildziukevich, Uladzimir,Kaletová, Eva,?aman, David,Siev?nen, Elina,Kolehmainen, Erkki T.,?louf, Miroslav,Wimmer, Zdeněk
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supporting information
p. 90 - 96
(2016/12/26)
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- Triterpenoid derivative TBA-X with antitumor effect as well as preparation method and application thereof
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The invention provides a compound with a structural general form 1 or 2, a preparation method thereof, and an application of the compound in preparation of antitumor drugs. The composition provided by the invention has a significant inhibitory action on liver cancer, stomach cancer, colon cancer, cervical cancer cell lines.
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Paragraph 0058; 0059; 0101; 0102; 0103
(2017/08/28)
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- NOVEL C28-ANALOGUES WITH C3-MODIFICATIONS OF TRITERPENE DERIVATIVES AS HIV INHIBITORS
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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.
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(2017/03/08)
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- Discovery of BMS-955176, a Second Generation HIV-1 Maturation Inhibitor with Broad Spectrum Antiviral Activity
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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.
- 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.
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supporting information
p. 568 - 572
(2016/07/06)
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- C-3 benzoic acid derivatives of C-3 deoxybetulinic acid and deoxybetulin as HIV-1 maturation inhibitors
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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.
- 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
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p. 1757 - 1770
(2016/04/05)
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- Polyamine derivatives of betulinic acid and β-sitosterol: A comparative investigation
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β-Sitosterol and betulinic acid were used in designing their conjugates with selected polyamines bearing either an amide bond, or an ester and an amide bond simultaneously in the target molecule. The synthesized compounds were subjected to basic cytotoxic and antimicrobial tests. The synthetic protocol is described separately for each of the three series of the target amides, because each series of compounds required a different synthetic approach. The cytotoxicity was tested on cells derived from human T-lymphoblastic leukemia, breast adenocarcinoma and cervical cancer, and compared with the tests on normal human fibroblasts. Most of the target compounds (5a-5c, 11a-11c and 16a-16c) showed medium to high cytotoxicity (0.7-7.8 μM), however, in some cases the compounds showed high cytotoxicity even toward normal human fibroblasts (11a-11c). Two compounds of this series (11c and 16c) also displayed antimicrobial activity with high and selective microbe specificity. The compound 11c was potent against Escherichia coli (minimal inhibition concentration (MIC) 6.25 μg mL-1, i.e. 9.75 nM mL-1) and Staphylococcus aureus (MIC 12.5 μg mL-1, i.e. 19.5 nM mL-1), and showed medium activity against Pseudomonas aeruginosa. The compound 16c was highly active against Enterococcus faecalis and S. aureus (both, MIC 3.125 μg mL-1, i.e. 4.22 nM mL-1), both Gram-positive bacteria, however showed only weak activity against E. coli and no activity against P. aeruginosa, both Gram-negative bacteria, which indicates possible microbe specificity of 16c. Comparing β-sitosterol-based series (5a-5c) and betulinic acid series (11a-11c and 16a-16c) of the target compounds, the latter one gave more promising structures. The compounds 11c and 16c showed effects which may be described as multifarious activity (pleiotropic effects).
- Bildziukevich, Uladzimir,Vida, Norbert,Rárová, Lucie,Kolá?, Milan,?aman, David,Havlí?ek, Libor,Dra?ar, Pavel,Wimmer, Zdeněk
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supporting information
p. 27 - 35
(2015/05/27)
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- C-19 MODIFIED TRITERPENOIDS WITH HIV MATURATION INHIBITORY ACTIVITY
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Compounds having drug and bio-affecting properties, their pharmaceutical compositions and methods of use are set forth. In particular, C-19 modified triterpenoids that possess unique antiviral activity are provided as HIV maturation inhibitors, as represented by compounds of Formulas I and II: These compounds are useful for the treatment of HIV and AIDS.
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(2014/08/19)
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- Improving Physical Properties via C-H Oxidation: Chemical and Enzymatic Approaches
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Physicochemical properties constitute a key factor for the success of a drug candidate. Whereas many strategies to improve the physicochemical properties of small heterocycle-type leads exist, complex hydrocarbon skeletons are more challenging to derivatize because of the absence of functional groups. A variety of C-H oxidation methods have been explored on the betulin skeleton to improve the solubility of this very bioactive, yet poorly water-soluble, natural product. Capitalizing on the innate reactivity of the molecule, as well as the few molecular handles present on the core, allowed oxidations at different positions across the pentacyclic structure. Enzymatic oxidations afforded several orthogonal oxidations to chemical methods. Solubility measurements showed an enhancement for many of the synthesized compounds. A handle on [O]: A variety of C-H oxidation methods were explored on the betulin skeleton to improve the solubility of this bioactive, yet poorly water-soluble, natural product. The innate reactivity of the molecule, as well as the molecular handles present on the core, allowed oxidations at different positions. Solubility enhancement was observed for many of the synthesized compounds.
- Michaudel, Quentin,Journot, Guillaume,Regueiro-Ren, Alicia,Goswami, Animesh,Guo, Zhiwei,Tully, Thomas P.,Zou, Lufeng,Ramabhadran, Raghunath O.,Houk, Kendall N.,Baran, Phil S.
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supporting information
p. 12091 - 12096
(2016/02/23)
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- C-17 BICYCLIC AMINES OF TRITERPENOIDS WITH HIV MATURATION INHIBITORY ACTIVITY
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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.
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Paragraph 0345-0346
(2013/11/19)
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- C-17 AND C-3 MODIFIED TRITERPENOIDS WITH HIV MATURATION INHIBITORY ACTIVITY
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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.
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(2012/08/27)
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- A partial synthesis of 23-hydroxybetulonic acid and 23-hydroxybetulinic acid starting from betulinic acid
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A partial syntheses of the biologically active 23-hydroxybetulonic acid and 23-hydroxybetulinic acid starting from the naturally abundant betulinic acid has been developed in which the key step was the Baldwin's cyclopalladation of the 23-methyl group from a 3-one oxime of betulinic acid, an important drug in Chinese medicine.
- Sun, Fei,Zhu, Peiqing,Yao, Hequan,Wu, Xiaoming,Xu, Jinyi
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experimental part
p. 254 - 257
(2012/10/08)
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- MODIFIED C-3 BETULINIC ACID DERIVATIVES AS HIV MATURATION INHIBITORS
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Compounds having drug and bio-affecting properties, their pharmaceutical compositions and methods of use are set forth. In particular, modified C-3 betulinic acid and other structurally related natural products derivatives that possess unique antiviral activity are provided as HIV maturation inhibitors. These compounds are useful for the treatment of HIV and AIDS.
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(2011/12/14)
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- C-28 AMIDES OF MODIFIED C-3 BETULINIC ACID DERIVATIVES AS HIV MATURATION INHIBITORS
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Compounds having drug and bio-affecting properties, their pharmaceutical compositions and methods of use are set forth. In particular, modified C-3 and C-28 betulinic acid derivatives that possess unique antiviral activity are provided as HIV maturation inhibitors. These compounds are useful for the treatment of HIV and AIDS.
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(2011/12/14)
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- Structure - Activity relationship study of betulinic acid, a novel and selective TGR5 agonist, and its synthetic derivatives: Potential impact in diabetes
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We describe here the biological screening of a collection of natural occurring triterpenoids against the G protein-coupled receptor TGR5, known to be activated by bile acids and which mediates some important cell functions. This work revealed that betulinic (1), oleanolic (2), and ursolic acid (3) exhibited TGR5 agonist activity in a selective manner compared to bile acids, which also activated FXR, the nuclear bile acid receptor. The most potent natural triterpenoid betulinic acid was chosen as a reference compound for an SAR study. Hemisyntheses were performed on the betulinic acid scaffold, and we focused on structural modifications of the C-3 alcohol, the C-17 carboxylic acid, and the C-20 alkene. In particular, structural variations around the C-3 position gave rise to major improvements of potency exemplified with derivatives 18 dia 2 (RG-239) and 19 dia 2. The best derivative was tested in vitro and in vivo, and its biological profile is discussed.
- Genet, Cédric,Strehle, Axelle,Schmidt, Céline,Boudjelal, Geoffrey,Lobstein, Annelise,Schoonjans, Kristina,Souchet, Michel,Auwerx, Johan,Saladin, Régis,Wagner, Alain
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experimental part
p. 178 - 190
(2010/04/30)
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- METHOD OF PREPARATION OF A SOLUBLE FORMULATION OF WATER-INSOLUBLE PENTACYCLIC AND TETRACYCLIC TERPENOIDS, A SOLUBLE FORMULATION OF A PENTACYCLIC OR TETRACYCLIC TERPENOID AND A PHARMACEUTICAL COMPOSITION CONTAINING THIS SOLUBLE FORMULATION
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The invention relates to a method of preparation of a soluble formulation of water-insoluble pentacyclic and tetracyclic terpenoids, wherein the water-insoluble terpenoid having a free carboxylic, hydroxy or amino functional group is derivatized on this functional group with a substituent selected from the group comprising substituents of general formula Xa bound to the hydroxy group of the terpenoid, wherein Xa is -OC-R-COOH, substituents of general formula Xa bound to the amino group of the terpenoid, wherein Xa is -OC-R-COOH, quarternary ammonium substituents of general formula Xb bound to the carboxy group of the terpenoid, wherein Xb is -(CH2)nN+R3Y-, quarternary ammonium substituents of general formula Xc bound to the carboxy group of the terpenoid, wherein Xc je -(CH2)nR+Y-, substituents of general formula Xd bound to the carboxy group of the terpenoid, wherein Xd represents -R-COOH, glycosylic substituents Xe bound by alpha or beta glycosidic bond to the hydroxy group or to the carboxy group of the terpenoid, wherein Xe is selected from the group comprising glucosyl, galactosyl, arabinosyl, rhamnosyl, lactosyl, cellobiosyl, maltosyl and the 2-deoxyanalogues thereof, and subsequently, the prepared derivative is dissolved in the solution containing water, a cyclodextrin and optionally pharmaceutically acceptable auxiliary substances, forming an inclusion derivative with the cyclodextrin. Object of the invention is further a soluble formulation of a pentacyclic or tetracyclic triterpenoid, containing an inclusion complex of the derivatized pentacyclic or tetracyclic terpenoid with a cyclodextrin, and optionally water and pharmaceutically acceptable auxiliary substances and further a pharmaceutical composition containing the soluble formulation.
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(2008/06/13)
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- Anti-AIDS agents - XXVII. Synthesis and anti-HIV activity of betulinic acid and dihydrobetulinic acid derivatives
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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.
- Hashimoto, Fumio,Kashiwada, Yoshiki,Cosentino, L. Mark,Chen, Chin-Ho,Garrett, Patricia E.,Lee, Kuo-Hsiung
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p. 2133 - 2143
(2007/10/03)
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