Design, Synthesis, and Biological Evaluation of Betulinic Acid Derivatives as Potent Anti-HIV-1 Agents

The overall goals of this research were to design and synthesize novel betulinic acid (BA) derivatives and to evaluate their biological activities, establish structure-activity relationships (SAR), and investigate mechanism(s) of action. Three specific goals were identified in this study: 1) establish the detailed SAR of C-3 modified BA analogs for HIV-1 maturation inhibitors and further improve antiviral activity profiles; 2) investigate the impacts of C-19 isopropenyl moiety to the antiviral activity and develop 28,30-disubstituted BA analogs as novel HIV-1 entry inhibitors; 3) develop 3,28-disubstituted BA analogs as bifunctional HIV-1 inhibitors. More than 50 BA derivatives were synthesized and evaluated in HIV-1 replication inhibition assay in this research. Compound 82 with enlarged C-3' substitution of C-3 side chain showed an extremely potent anti-HIV-1 activity with an EC50 value of 0.0006 μM, which was better than the current clinical trial candidates bevirimat (DSB) in HIV-1IIIB infected MT-2 cell line. In contrast, C-30 substitutions through ether bond do not influence the antiviral potency of the derivatives significantly. Incorporation of water-solubilizing moieties into C-30 position can improve the hydropholicity and solubility of the C-28 modified BA derived HIV-1 entry inhibitors significantly, which led to the discovery of 112 with a significant anti-HIV-1 activity (EC50: 0.09 μM) similar to the previous best hints. The C-28 side chain was further modified to increase the metabolic stability, resulting in the identification of novel 3,28-disubstituted BA analogs 131 and 132, with better stability and extremely potent antiviral activities (EC50 ~0.006 μM) which are slightly better than that of bevirimat. In a different project, we discovered that C-3 modification and C-30 modification can increase the anti-proteasome activity of BA dramatically. 3,30-disubstituted BA analogs may be developed into potent proteasome inhibitors and potential anti-cancer agents, which represents another promising direction for the development of BA derivatives

HIV entry inhibitors and their potential in HIV therapy

This review discusses recent progress in the development of anti-HIV agents targeting the viral entry process. The three main classes (attachment inhibitors, co-receptor binding inhibitors, and fusion inhibitors) are further broken down by specific mechanism of action and structure. Many of these inhibitors are in advanced clinical trials, including the HIV maturation inhibitor bevirimat, from the authors’ laboratories. In addition, the CCR5 inhibitor maraviroc has recently been FDA-approved. Possible roles for these agents in anti-HIV therapy, including treatment of virus resistant to current drugs, are also discussed

Anti-AIDS agents 73: Structure–activity relationship study and asymmetric synthesis of 3-O-monomethylsuccinyl-betulinic acid derivatives

3-O-3′(or 2′)-methylsuccinyl-betulinic acid (MSB) derivatives were separated by using recycle HPLC. The structures of four isomers were assigned by NMR and asymmetric synthesis. 3-O-3′S-Methylsuccinyl-betulinic acid (3′S-MSB, 4) exhibited potent anti-HIV activity with an EC50 value of 0.0087 μM and a TI value of 6.3×103, which is comparable to the data for bevirimat (DSB, PA-457), a current clinical trials drug that was also derived from betulinic acid. The anti-HIV potency of 4 was slightly better than that of AZT

Anti-AIDS Agents 90. Novel C-28 Modified Bevirimat Analogues as Potent HIV Maturation Inhibitors

In a continuing study of bevirimat (2), the anti-HIV-maturation clinical trials agent, 28 new betulinic acid (BA, 1) derivatives were designed and synthesized. Among these compounds, 17, with a C-28 MEM ester moiety, and 22, with a C-28 ethyl hexanoate, increased the anti-HIV replication activity compared with 2 by two-fold, while compounds 40–41 and 48–49, with C-28 piperazine or piperidine amide substitutions, increased the activity by three- to fifteen-fold. The best new compound 41 exhibited an anti-HIV IC50 value of 0.0059 μM, compared with 0.087 μM for 2. All of the active compounds showed only anti-maturation effects, as confirmed by TZM-bl assay, in blocking the HIV replication. The results suggest that proper C-28 substitutions can further enhance the anti-maturation activity of 2, without any anti-entry effects. Thus, 41 may serve as a promising new lead for development of anti-AIDS clinical trial candidates

Plant-derived triterpenoids and analogues as antitumor and anti-HIV agents

This article reviews the antitumor and anti-HIV activities of naturally occurring triterpenoids, including the lupane, ursane, oleanane, lanostane, dammarane, and miscellaneous scaffolds. Structure–activity relationships of selected natural compounds and their synthetic derivatives are also discussed

Synthesis and proteasome inhibition of glycyrrhetinic acid derivatives

This study discovered that glycyrrhetinic acid inhibited the human 20S proteasome at 22.3 µM. Esterification of the C-3 hydroxyl group on glycyrrhetinic acid with various carboxylic acid reagents yielded a series of analogs with marked improved potency. Among the derivatives, glycyrrhetinic acid 3-O-isophthalate (17) was the most potent compound with IC50 of 0.22 µM, which was approximately 100-fold more potent than glycyrrhetinic acid

Synthesis of Lithocholic Acid Derivatives as Proteasome Regulators

Accumulation of aberrant protein aggregates, such as amyloid β peptide (Aβ), due to decreased proteasome activities, might contribute to the neurodegeneration in Alzheimer's disease. In this study, lithocholic acid derivatives 3α-O-pimeloyl-lithocholic acid methyl ester (2) and its isosteric isomer (6) were found to activate the chymotrypsin-like activity of the proteasome at an EC50 of 7.8 and 4.3 μM, respectively. Replacing the C24 methyl ester in 2 with methylamide resulted in a complete devoid of proteasome activating activity. Epimerizing the C3 substituent from an α to β orientation transformed the activator into a proteasome inhibitor. Unlike the cellular proteasome activator PA28, proteasome activated by 2 was not inhibited by Aβ. Furthermore, 2 potently antagonized the inhibitory effect of Aβ on the proteasome. In summary, compound 2 represents a novel class of small molecules that not only activates the proteasome but also antagonizes the inhibitory effect of Aβ on the proteasome

Synthesis and anti-HIV activity of 2′-deoxy-2′-fluoro-4′-C-ethynyl nucleoside analogs

Based on the favorable antiviral profiles of 4′-substituted nucleosides, novel 1-(2′-deoxy-2′-fluoro-4′-C-ethynyl-β-D-arabinofuranosyl)-uracil (1a), -thymine (1b), and – cytosine (2) analogues were synthesized. Compounds 1b and 2 exhibited potent anti-HIV-1 activity with IC50 values of 86 and 1.34 nM, respectively, without significant cytotoxicity. Compound 2 was 35-fold more potent than AZT against wild-type virus, and also retained nanomolar antiviral activity against resistant strains, NL4-3(K101E) and RTMDR. Thus, 2 merits further development as a novel NRTI drug

New betulinic acid derivatives as potent proteasome inhibitors

In this study, 22 new betulinic acid (BA) derivatives were synthesized and tested for their inhibition of the chymotrypsin-like activity of 20S proteasome. From the SAR study, we concluded that the C-3 and C-30 positions are the pharmacophores for increasing the proteasome inhibition effects, and larger lipophilic or aromatic side chains are favored at these positions. Among the BA derivatives tested, compounds 13, 20, and 21 showed the best proteasome inhibition activity with IC50 values of 1.42, 1.56, and 1.80 µM, respectively, which are three- to four-fold more potent than the proteasome inhibition controls LLM-F and lactacystin

Betulinic Acid Derivatives as Human Immunodeficiency Virus Type 2 (HIV-2) Inhibitors ∥

We previously reported that [[N-[3β-hydroxyl-lup-20(29)-en-28-oyl]-7-aminoheptyl]-carbamoyl]methane (A43D, 4) was a potent HIV-1 entry inhibitor. However, 4 was inactive against HIV-2 virus, suggesting the structural requirements for targeting these two retroviruses are different. In this study, a series of new betulinic acid derivatives were synthesized, and some of them displayed selective anti-HIV-2 activity at nanomolar concentrations. In comparison to compounds with anti-HIV-1 activity, a shorter C-28 side chain is required for optimal anti-HIV-2 activity