RESUMEN
Pentosan polysulfate sodium (PPS) is an orphan drug with anticoagulant activity. PPS is prepared from the chemical processing of xylan extracted from beechwood tree to yield a mixture of 4-6 kDa polysaccharides. The chain is mainly composed of sulfated xylose (Xyl) with branched 4-O-methyl-glucuronate (MGA). During generic drug development, the quality attributes (QAs) including monosaccharide composition, modification, and length need to be comparable to those found in the reference list drug (RLD). However, the range of QA variation of the RLD PPS has not been well characterized. Here, multiple PPS RLD lots were studied using quantitative NMR (qNMR) and diffusion ordered spectroscopy (DOSY) to quantitate the components in the mixture and to probe both inter- and intra-lot precision variability. The DOSY precision assessed using coefficient of variation (CV) was 6%, comparable to PPS inter-lot CV of 5%. The QAs obtained from 1D qNMR were highly precise with a precision CV < 1%. The inter-lot MGA content was 4.8 ± 0.1%, indicating a very consistent botanical raw material source. Other process-related chemical modification including aldehyde at 0.51 ± 0.04%, acetylation at 3.3 ± 0.2% and pyridine at 2.08 ± 0.06%, varied more than MGA content. The study demonstrated that 1D qNMR is a quick and precise method to reveal ranges of variation in multiple attributes of RLD PPS which can be used to assess equivalency with generic formulations. Interestingly, the synthetic process appeared to introduce more variations to the PPS product than the botanical source of the material.
Asunto(s)
Imagen por Resonancia Magnética , Poliéster Pentosan Sulfúrico , Espectroscopía de Resonancia MagnéticaRESUMEN
[This corrects the article DOI: 10.18632/oncotarget.3701.].
RESUMEN
Herein, we evaluated the anti-cancer effect and molecular mechanisms of a novel betulinic acid (BA) derivative, SYK023, by using two mouse models of lung cancer driven by KrasG12D or EGFRL858R. We found that SYK023 inhibits lung tumor proliferation, without side effects in vivo or cytotoxicity in primary lung cells in vitro. SYK023 triggered endoplasmic reticulum (ER) stress. Blockage of ER stress in SYK023-treated cells inhibited SYK023-induced apoptosis. In addition, we found that the expression of cell cycle-related genes, including cyclin A2, B1, D3, CDC25a, and CDC25b decreased but, while those of p15INK4b, p16INK4a, and p21CIP1 increased following SYK023 treatment. Finally, low doses of SYK023 significantly decreased lung cancer metastasis in vitro and in vivo. Expression of several genes related to cell migration, including synaptopodin, were downregulated by SYK023, thereby impairing F-actin polymerization and metastasis. Therefore, SYK023 may be a potentially therapeutic treatment for metastatic lung cancer.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Triterpenos/farmacología , Animales , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Humanos , Neoplasias Pulmonares/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones SCID , Ratones Transgénicos , Metástasis de la Neoplasia , Triterpenos Pentacíclicos , Pronóstico , Transfección , Ensayos Antitumor por Modelo de Xenoinjerto , Ácido BetulínicoRESUMEN
Camptothecins (CPTs) are cytotoxic natural alkaloids that specifically target DNA topoisomerase I. Research on CPTs has undergone a significant evolution from the initial discovery of CPT in the late 1960s through the study of synthetic small-molecule derivatives to investigation of macromolecular constructs and formulations. Over the past years, intensive medicinal chemistry efforts have generated numerous CPT derivatives. Three derivatives, topotecan, irinotecan, and belotecan, are currently prescribed as anticancer drugs, and several related compounds are now in clinical trials. Interest in other biological effects, besides anticancer activity, of CPTs is also growing exponentially, as indicated by the large number of publications on the subject during the last decades. Therefore, the main focus of the present review is to provide an ample but condensed overview on various biological activities of CPT derivatives, in addition to continued up-to-date coverage of anticancer effects.
Asunto(s)
Camptotecina/farmacología , Antiinfecciosos/química , Antiinfecciosos/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Camptotecina/química , HumanosRESUMEN
Podophyllotoxin (PPT), as well as its congeners and derivatives, exhibits pronounced biological activities, especially antineoplastic effects. Its strong inhibitory effect on tumor cell growth led to the development of three of the most highly prescribed anticancer drugs in the world, etoposide, teniposide, and the water-soluble prodrug etoposide phosphate. Their clinical success as well as intriguing mechanism of action stimulated great interest in further modification of PPT for better antitumor activity. The C-4 position has been a major target for structural derivatization aimed at either producing more potent compounds or overcoming drug resistance. Accordingly, numerous PPT derivatives have been prepared via hemisynthesis and important structure-activity relationship (SAR) correlations have been identified. Several resulting compounds, including GL-331, TOP-53, and NK611, reached clinical trials. Some excellent reviews on the distribution, sources, applications, synthesis, and SAR of PPT have been published. This review focuses on a second generation of new etoposide-related drugs and provides detailed coverage of the current status and recent development of C-4-modified PPT analogs as anticancer clinical trial candidates.
Asunto(s)
Antineoplásicos/química , Podofilotoxina/análogos & derivados , Animales , Antineoplásicos/farmacología , Humanos , Podofilotoxina/química , Podofilotoxina/farmacología , Relación Estructura-ActividadRESUMEN
Twelve novel 20-sulfonylamidine derivatives (9a-9l) of camptothecin (1) were synthesized via a Cu-catalyzed three-component reaction. They showed similar or superior cytotoxicity compared with that of irinotecan (3) against A-549, DU-145, KB, and multidrug-resistant (MDR) KBvin tumor cell lines. Compound 9a demonstrated better cytotoxicity against MDR cells compared with that of 1 and 3. Mechanistically, 9a induced significant DNA damage by selectively inhibiting Topoisomerase (Topo) I and activating the ATM/Chk related DNA damage-response pathway. In xenograft models, 9a demonstrated significant activity without overt adverse effects at 5 and 10 mg/kg, comparable to 3 at 100 mg/kg. Notably, 9a at 300 mg/kg (i.p.) showed no overt toxicity in contrast to 1 (LD50 56.2 mg/kg, i.p.) and 3 (LD50 177.5 mg/kg, i.p.). Intact 9a inhibited Topo I activity in a cell-free assay in a manner similar to that of 1, confirming that 9a is a new class of Topo I inhibitor. 20-Sulfonylamidine 1-derivative 9a merits development as an anticancer clinical trial candidate.
Asunto(s)
Amidinas/química , Antineoplásicos/farmacología , Camptotecina/análogos & derivados , ADN-Topoisomerasas de Tipo I/metabolismo , Diseño de Fármacos , Neoplasias Experimentales/tratamiento farmacológico , Sulfonamidas/química , Inhibidores de Topoisomerasa I/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Camptotecina/química , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Células HCT116 , Humanos , Células KB , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Conformación Molecular , Neoplasias Experimentales/patología , Relación Estructura-Actividad , Inhibidores de Topoisomerasa I/síntesis química , Inhibidores de Topoisomerasa I/químicaRESUMEN
Nineteen new halogenated diarylpyridinamine (DAPA) analogues modified at the phenoxy C-ring were synthesized and evaluated for anti-HIV activity and certain drug-like properties. Ten compounds showed high anti-HIV activity (EC50 <10â nM). In particular, (E)-6-(2''-bromo-4''-cyanovinyl-6''-methoxy)phenoxy-N(2) -(4'-cyanophenyl)pyridin-2,3-diamine (8 c) displayed low-nanomolar antiviral potency (3-7â nM) against wild-type and drug-resistant viral strains bearing the E138K or K101E mutations, which are associated with resistance to rilvipirine (1 b). Compound 8 c exhibited much lower resistance fold changes (RFC: 1.1-2.1) than 1 b (RFC: 11.8-13.0). Compound 8 c also exhibited better metabolic stability (in vitro half-life) than 1 b in human liver microsomes, possessed low lipophilicity (clog D: 3.29; measured log P: 3.31), and had desirable lipophilic efficiency indices (LE>0.3, LLE>5, LELP<10). With balanced potency and drug-like properties, 8 c merits further development as an anti-HIV drug candidate.
Asunto(s)
Aminas/química , Transcriptasa Inversa del VIH/antagonistas & inhibidores , VIH-1/enzimología , Inhibidores de la Transcriptasa Inversa/química , Aminas/metabolismo , Aminas/farmacología , Diseño de Fármacos , Transcriptasa Inversa del VIH/genética , Transcriptasa Inversa del VIH/metabolismo , VIH-1/efectos de los fármacos , Semivida , Halogenación , Humanos , Microsomas Hepáticos/metabolismo , Mutación , Pirimidinas/química , Inhibidores de la Transcriptasa Inversa/metabolismo , Inhibidores de la Transcriptasa Inversa/farmacología , Relación Estructura-ActividadRESUMEN
The 6-methoxy-1,2,3,4-tetrahydroquinoline moiety in prior leads 2-chloro- and 2-methyl-4-(6-methoxy-3,4-dihydroquinolin-1(2H)-yl)quinazoline (1a and 1b) was modified to produce 4-(N-cycloamino)quinazolines (4a-c and 5a-m). The new compounds were evaluated in cytotoxicity and tubulin inhibition assays, resulting in the discovery of new tubulin-polymerization inhibitors. 7-Methoxy-4-(2-methylquinazolin-4-yl)-3,4-dihydroquinoxalin- 2(1H)-one (5f), the most potent compound, exhibited high in vitro cytotoxic activity (GI50 1.9-3.2 nM), significant potency against tubulin assembly (IC50 0.77 µM), and substantial inhibition of colchicine binding (99% at 5 µM). In mechanism studies, 5f caused cell arrest in G2/M phase, disrupted microtubule formation, and competed mostly at the colchicine site on tubulin. Compound 5f and N-methylated analogue 5g were evaluated in nude mouse MCF7 xenograft models to validate their antitumor activity. Compound 5g displayed significant in vivo activity (tumor inhibitory rate 51%) at a dose of 4 mg/kg without obvious toxicity, whereas 5f unexpectedly resulted in toxicity and death at the same dose.
Asunto(s)
Colchicina/química , Quinazolinas/farmacología , Moduladores de Tubulina/farmacología , Animales , Proliferación Celular/efectos de los fármacos , Femenino , Concentración 50 Inhibidora , Espectroscopía de Resonancia Magnética , Ratones , Ratones Desnudos , Modelos Moleculares , Quinazolinas/química , Espectrometría de Masa por Ionización de Electrospray , Relación Estructura-Actividad , Moduladores de Tubulina/químicaRESUMEN
Ten new 3,4-seco betulinic acid (BA) derivatives were designed and synthesized. Among them, compounds 7-15 exhibited enhanced chemopreventive ability in an in vitro short-term 12-O-tetradecanoylphorbol-13-acetate (TPA) induced Epstein-Barr virus early antigen (EBV-EA) activation assay in Raji cells. Specifically, analogs with a free C-28 carboxylic acid, including 7, 8, 11, and 13, inhibited EBV-EA activation significantly. The most potent compound 8 displayed 100% inhibition at 1×10(3) mol ratio/TPA and 73.4%, 35.9%, and 8.4% inhibition at 5×10(2), 1×10(2), and 1×10 mol ratio/TPA, respectively, comparable with curcumin at high concentration and better than curcumin at low concentration. The potent chemopreventive activity of novel seco A-ring BAs (8 and 11) was further confirmed in an in vivo mouse skin carcinogenesis assay.
Asunto(s)
Anticarcinógenos/química , Anticarcinógenos/farmacología , Neoplasias/prevención & control , Triterpenos/química , Triterpenos/farmacología , Animales , Línea Celular , Herpesvirus Humano 4/efectos de los fármacos , Humanos , Ratones , Triterpenos Pentacíclicos , Triterpenos/síntesis química , Ácido BetulínicoRESUMEN
Structural optimizations of the prior lead 1a led to the discovery of a series of N-aryl-6-methoxy-1,2,3,4-tetrahydroquinoline derivatives as a novel class of tubulin polymerization inhibitors targeted at the colchicine binding site. The most active compound 6d showed extremely high cytotoxicity against a human tumor cell line panel (A549, KB, KBvin, and DU145) with GI50 values ranging from 1.5 to 1.7 nM, significantly more potent than paclitaxel, especially against the drug-resistant KBvin cell line, in the same assays. Analogs 5f, 6b, 6c, and 6e were also quite potent, with a GI50 range of 0.011-0.19 µM. In further studies, active compounds 6b-e and 5f significantly inhibited tubulin assembly, with IC50 values of 0.92-1.0 µM and strongly inhibited colchicine binding to tubulin, with inhibition rates of 75-99% (at 5 µM), comparable with or more potent than combretastatin A-4 (IC50 0.96 µM). Current studies included design, synthesis, and biological evaluations of 24 new compounds (series 3-6). Related SAR analysis, molecular modeling, and evaluation of essential drug-like properties, i.e. water solubility, log P, and in vitro metabolic stability, were also performed.
Asunto(s)
Antineoplásicos/farmacología , Colchicina/química , Quinolinas/farmacología , Tubulina (Proteína)/metabolismo , Antineoplásicos/síntesis química , Antineoplásicos/química , Sitios de Unión/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Células KB , Modelos Moleculares , Estructura Molecular , Polimerizacion/efectos de los fármacos , Quinolinas/síntesis química , Quinolinas/química , Relación Estructura-Actividad , Tubulina (Proteína)/químicaRESUMEN
Five novel tigliane-type diterpenes, stelleracins A-E (3-7), a novel flavanone dimer, chamaeflavone A (8), and six known compounds were isolated from the roots of Stellera chamaejasme. Their structures were elucidated by extensive spectroscopic analyses. The isolated compounds were evaluated for anti-HIV activity in MT4 cells. New compounds 3-5 showed potent anti-HIV activity (EC90 0.00056-0.0068 µM) and relatively low or no cytotoxicity (IC50 4.4-17.2 µM). These new compounds represent promising new leads for development into anti-AIDS clinical trial candidates.
Asunto(s)
Fármacos Anti-VIH/aislamiento & purificación , Fármacos Anti-VIH/farmacología , Diterpenos/aislamiento & purificación , Diterpenos/farmacología , Flavanonas/aislamiento & purificación , Flavanonas/farmacología , Thymelaeaceae/química , Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Fármacos Anti-VIH/química , Supervivencia Celular/efectos de los fármacos , Diterpenos/química , Flavanonas/química , Estructura Molecular , Nepal , Resonancia Magnética Nuclear Biomolecular , Raíces de Plantas/químicaRESUMEN
Twenty new acyl thiourea derivatives of podophyllotoxin and 4'-demethylepipodophyllotoxin were prepared and screened for their cytotoxicity against four human tumor cell lines, A-549, DU-145, KB, and KBvin. With IC50 values of 0.098-1.13 µM, compounds 13b, 13c, and 13o displayed much better cytotoxic activity than the control etoposide. Most importantly, 13b and 13o exhibited promising cytotoxicity against the drug resistant tumor cell line KBvin with IC50 values of 0.098 and 0.13 µM, respectively, while etoposide lost activity completely. Structure-activity relationship (SAR) correlations of the new derivatives have been established. Compounds 13b and 13o merit further development as a new generation of epipodophyllotoxin-derived antitumor clinical trial candidates.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Podofilotoxina/análogos & derivados , Podofilotoxina/farmacología , Antineoplásicos/síntesis química , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Células KB , Podofilotoxina/síntesis química , Podofilotoxina/química , Relación Estructura-Actividad , Tiourea/análogos & derivados , Tiourea/síntesis química , Tiourea/química , Tiourea/farmacología , Inhibidores de Topoisomerasa II/síntesis química , Inhibidores de Topoisomerasa II/química , Inhibidores de Topoisomerasa II/farmacologíaRESUMEN
Bevirimat (1, BVM) is an anti-HIV agent that blocks HIV-1 replication by interfering with HIV-1 Gag-SP1 processing at a late stage of viral maturation. However, clinical trials of 1 have revealed a high baseline drug resistance that is attributed to naturally occurring polymorphisms in HIV-1 Gag. To overcome the drug resistance, 28 new derivatives of 1 were synthesized and tested against compound 1-resistant (BVM-R) HIV-1 variants. Among them, compound 6 exhibited much improved activity against several HIV-1 strains carrying BVM-R polymorphisms. Compound 6 was at least 20-fold more potent than 1 against the replication of NL4-3/V370A, which carries the most prevalent clinical BVM-R polymorphism in HIV-1 Gag-SP1. Thus, compound 6 merits further development as a potential anti-AIDS clinical trial candidate.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Fármacos Anti-VIH/uso terapéutico , VIH-1/efectos de los fármacos , Succinatos/uso terapéutico , Triterpenos/uso terapéutico , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/genética , Fármacos Anti-VIH/farmacología , Línea Celular , Farmacorresistencia Viral , VIH-1/genética , Humanos , Polimorfismo Genético , Triterpenos/síntesis química , Replicación Viral/efectos de los fármacosRESUMEN
Eighteen novel spin-labeled 18ß-glycyrrhetinic acid (GA) derivatives were designed, synthesized, and evaluated for cytotoxicity against four human tumor cell lines (A-549, DU-145, KB and KBvin). Most of the derivatives showed more significant cytotoxicity than that of the parent compound GA. The best compound, 6j, with a tryptophan amino moiety and piperidine nitroxyl radical showed GI(50) values of 13.7-15.0 µM, and was fivefold more potent than GA. In a mechanism of action study, compound 7a was confirmed as a 20S proteasome inhibitor in both in vitro and cell-based assays. These findings support further optimization efforts based on 18ß-GA as a lead compound to develop potential anticancer drug candidates.
Asunto(s)
Antineoplásicos/farmacología , Ácido Glicirretínico/análogos & derivados , Complejo de la Endopetidasa Proteasomal/metabolismo , Inhibidores de Proteasoma/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Ácido Glicirretínico/síntesis química , Ácido Glicirretínico/química , Ácido Glicirretínico/farmacología , Humanos , Conformación Molecular , Inhibidores de Proteasoma/síntesis química , Inhibidores de Proteasoma/química , Relación Estructura-ActividadRESUMEN
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 2-fold while compounds 40, 41, 48, and 49, with C-28 piperazine or piperidine amide substitutions, increased the activity by 3- to 15-fold. The best new compound, 41, exhibited an anti-HIV IC(50) of 0.0059 µM compared with 0.087 µM for 2. All of the active compounds showed only antimaturation effects, as confirmed by TZM-bl assay, in blocking the HIV replication. The results suggest that proper C-28 substitutions can further enhance the antimaturation activity of 2 without any antientry effects. Thus, 41 may serve as a promising new lead for development of anti-AIDS clinical trial candidates.
Asunto(s)
Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacología , VIH-1/efectos de los fármacos , VIH-1/fisiología , Succinatos/química , Succinatos/farmacología , Triterpenos/química , Triterpenos/farmacología , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/toxicidad , Línea Celular , Diseño de Fármacos , Estabilidad de Medicamentos , Humanos , Relación Estructura-Actividad , Succinatos/síntesis química , Succinatos/toxicidad , Triterpenos/síntesis química , Triterpenos/toxicidad , Replicación Viral/efectos de los fármacosRESUMEN
Based on a shared structural core of diarylamine in several known anticancer drugs as well as a new cytotoxic hit 6-chloro-2-(4-cyanophenyl)amino-3-nitropyridine (7), 30 diarylamines and diarylethers were designed, synthesized, and evaluated for cytotoxic activity against A549, KB, KB-vin, and DU145 human tumor cell lines (HTCL). Four new leads 11e, 12, 13a, and 13b were discovered with GI(50) values ranging from 0.33 to 3.45µM. Preliminary SAR results revealed that a diarylamine or diarylether could serve as an active structural core, meta-chloro and ortho-nitro groups on the A-ring (either pyridine or phenyl ring) were necessary and crucial for cytotoxic activity, and the para-substituents on the other phenyl ring (B-ring) were related to inhibitory selectivity for different tumor cells. In an investigation of potential biological targets of the new leads, high thoughput kinase screening discovered that new leads 11e, 12 and 13b especially inhibit Mer tyrosine kinase, a proto-oncogene associated with munerous tumor types, with IC(50) values of 2.2-3.0µM. Therefore, these findings provide a good starting point to optimize a new class of compounds as potential anticancer agents, particularly targeting Mer tyrosine kinase.
Asunto(s)
Aminas/farmacología , Antineoplásicos/farmacología , Diseño de Fármacos , Éteres/farmacología , Aminas/síntesis química , Aminas/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Éteres/síntesis química , Éteres/química , Humanos , Estructura Molecular , Proto-Oncogenes Mas , Relación Estructura-ActividadRESUMEN
Twenty-one new 4-substituted diarylaniline compounds (DAANs) (series 13, 14, and 15) were designed, synthesized, and evaluated against wild-type and drug resistant HIV-1 viral strains. As a result, approximately a dozen new DAANs showed high potency with low nano- to subnanomolar EC(50) values ranging from 0.2 to 10 nM. The three most promising compounds 14e, 14h, and 15h exhibited high potency against wild-type and drug-resistant viral strains with EC(50) values at the subnanomolar level (0.29-0.87 nM) and were comparable to or more potent than the new NNRTI drug riplivirine (2) in the same assays. Druglike physicochemical property assessments revealed that the most active DAANs (EC(50) < 10 nM) have better aqueous solubility (>1-90 µg/mL at pH 7.4 and pH 2) and metabolic stability in vitro than 2, as well as desirable log P values (<5) and polar surface areas (PSA) (<140 Å(2)). These promising results warrant further development of this novel compound class as potential potent anti-AIDS clinical trial candidates.
Asunto(s)
Compuestos de Anilina/síntesis química , Fármacos Anti-VIH/síntesis química , Transcriptasa Inversa del VIH/metabolismo , VIH-1/efectos de los fármacos , Inhibidores de la Transcriptasa Inversa/síntesis química , Compuestos de Anilina/química , Compuestos de Anilina/farmacología , Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacología , Línea Celular , Diseño de Fármacos , Farmacorresistencia Viral , VIH-1/genética , Humanos , Técnicas In Vitro , Microsomas Hepáticos/metabolismo , Mutación , Inhibidores de la Transcriptasa Inversa/química , Inhibidores de la Transcriptasa Inversa/farmacología , Solubilidad , Estereoisomerismo , Relación Estructura-Actividad , Replicación ViralRESUMEN
Betulinic acid derivatives modified at the C28 position are HIV-1entry inhibitors such as compound A43D; however, modified at the C3 position instead of C28 give HIV-1 maturation inhibitor such as bevirimat. Bevirimat exhibited promising pharmacokinetic profiles in clinical trials, but its effectiveness was compromised by the high baseline drug resistance of HIV-1 variants with polymorphism in the putative drug binding site. In an effort to determine whether the viruses with bevirimat resistant polymorphism also altered their sensitivities to the betulinic acid derivatives that inhibit HIV-1 entry, a series of new betulinic acid entry inhibitors were synthesized and tested for their activities against HIV-1 NL4-3 and NL4-3 variants resistant to bevirimat. The results show that the bevirimat resistant viruses were approximately 5- to10-fold more sensitive to three new glutamine ester derivatives (13, 15 and 38) and A43D in an HIV-1 multi-cycle replication assay. In contrast, the wild type NL4-3 and the bevirimat resistant variants were equally sensitive to the HIV-1 RT inhibitor AZT. In addition, these three new compounds markedly improved microsomal stability compared to A43D.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Farmacorresistencia Viral/efectos de los fármacos , Glutamina/análogos & derivados , VIH-1/efectos de los fármacos , Triterpenos/síntesis química , Secuencia de Aminoácidos , Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacología , Glutamina/síntesis química , Glutamina/química , Glutamina/farmacología , Humanos , Microsomas Hepáticos/metabolismo , Triterpenos Pentacíclicos , Relación Estructura-Actividad , Triterpenos/química , Triterpenos/farmacología , Internalización del Virus/efectos de los fármacos , Ácido BetulínicoRESUMEN
In the present study, a new strategy to link AZT with betulin/betulinic acid (BA) by click chemistry was designed and achieved. This conjugation via a triazole linkage offers a new direction for modification of anti-HIV triterpenes. Click chemistry provides an easy and productive way for linking two molecules, even when one of them is a large natural product. Among the newly synthesized conjugates, compounds 15 and 16 showed potent anti-HIV activity with EC(50) values of 0.067 and 0.10 µM, respectively, which are comparable to that of AZT (EC(50): 0.10 µM) in the same assay.
RESUMEN
Covering: 2005 to 2010. This review covers recent discoveries of anti-diabetic compounds. Diabetes mellitus (DM) is a complex disease affecting patients' daily life and elevating patients' risk of developing other diseases. There are several forms of diabetes, including type-1 diabetes (insulin-dependent), type-2 diabetes (noninsulin-dependent), and gestational diabetes. Type-2 diabetes is the most common form and the patient population with type-2 DM rises every year. Current treatments meet some but not all patients' needs. Therefore, new anti-diabetic drugs are in great demand. Traditional herbal medicine provides a rich source for new drug discovery. In this review, recent discoveries of anti-diabetic compounds have been summarized according to their chemical structures and mechanisms of action. Anti-diabetic plant extracts, many of which have been used and marketed as dietary supplements, were also included and discussed, and are classified according to the positive control used in the anti-diabetic animal studies. New anti-diabetic natural products found in the recent patent literature are also summarized.