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1.
Magn Reson Chem ; 51(3): 156-67, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23364799

RESUMO

The (1)H and (13)C NMR spectra of 10-deoxymethynolide (1), 8.9-dihydro-10-deoxymethynolide (2) and its glycosylated derivatives (3-9) were analyzed using gradient-selected NMR techniques, including 1D TOCSY, gCOSY, 1D NOESY (DPFGSENOE), NOESY, gHMBC, gHSQC and gHSQC-TOCSY. The NMR spectral parameters (chemical shifts and coupling constants) of 1-9 were determined by iterative analysis. For the first time, complete and unambiguous assignment of the (1)H NMR spectrum of 10-deoxymethynolide (1) has been achieved in CDCl(3), CD(3)OD and C(6)D(6) solvents. The (1)H NMR spectrum of 8,9-dihydro-10-deoxymethynolide (2) was recorded in CDCl(3), (CD(3))(2)CO and CD(3)OD solutions to determine the conformation. NMR-based conformational analysis of 1 and 2 in conjugation with molecular modeling concluded that the 12-membered ring of the macrolactones may predominantly exist in a single stable conformation in all solvents examined. In all cases, a change in solvent caused only small changes in chemical shifts and coupling constants, suggesting that all glycosylated methymycin analogs exist with similar conformations of the aglycone ring in solution.


Assuntos
Macrolídeos/análise , Deutério , Glicosilação , Hidrogênio , Espectroscopia de Ressonância Magnética/normas , Modelos Moleculares , Conformação Molecular , Padrões de Referência , Estereoisomerismo
2.
Org Lett ; 22(4): 1448-1452, 2020 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-32009414

RESUMO

An asymmetric synthesis of two analogues of SL0101 (1) has been achieved. The effort is aimed at the discovery of inhibitors of the p90 ribosomal S6 kinase (RSK) with improved bioavailability. The route relies upon the use of the Taylor catalyst to regioselectively install C-3″ acetyl or carbamate functionality. This study led to the identification of a third-generation analogue of SL0101 with a C-4″ n-Pr-carbamate and a C-3″ acetate with improved RSK inhibitory activity.


Assuntos
Benzopiranos/farmacologia , Monossacarídeos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases S6 Ribossômicas 90-kDa/antagonistas & inibidores , Benzopiranos/síntese química , Benzopiranos/química , Estrutura Molecular , Monossacarídeos/síntese química , Monossacarídeos/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Estereoisomerismo
3.
J Theor Biol ; 253(1): 90-7, 2008 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-18397794

RESUMO

A novel descriptor, vector of principal component scores (VSW) for weighted holistic invariant molecular index, was derived from the principal component analysis of a matrix of 99 weighted holistic invariant molecular indices of amino acids. The scale was then applied in three panels of peptide QSARs models constructed by partial least square (PLS). The correlative coefficient R(cum)(2) and the cross-validation correlative coefficient Q(LOO)(2) of three models were 0.861 and 0.835 for 58 angiotensin-converting enzyme inhibitors, 0.873 and 0.751 for 48 bitter tasting thresholds, 0.997 and 0.954 for 12 antimicrobial polypeptides, respectively. External validation was also performed to validate the predictive power of resulting models. Compared with other 2D or 3D descriptors, the VSW scales could better characterize structural features of peptides and provide more sound statistical models.


Assuntos
Aminoácidos/química , Modelos Moleculares , Peptídeos/química , Relação Quantitativa Estrutura-Atividade , Análise dos Mínimos Quadrados , Estrutura Molecular , Biblioteca de Peptídeos , Análise de Componente Principal
4.
J Med Chem ; 60(12): 5045-5056, 2017 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-28525279

RESUMO

Human immunodeficiency virus (HIV) reverse transcriptase (RT)-associated ribonuclease H (RNase H) remains the only virally encoded enzymatic function yet to be exploited as an antiviral target. One of the possible challenges may be that targeting HIV RNase H is confronted with a steep substrate barrier. We have previously reported a 3-hydroxypyrimidine-2,4-dione (HPD) subtype that potently and selectively inhibited RNase H without inhibiting HIV in cell culture. We report herein a critical redesign of the HPD chemotype featuring an additional wing at the C5 position that led to drastically improved RNase H inhibition and significant antiviral activity. Structure-activity relationship (SAR) concerning primarily the length and flexibility of the two wings revealed important structural features that dictate the potency and selectivity of RNase H inhibition as well as the observed antiviral activity. Our current medicinal chemistry data also revealed that the RNase H biochemical inhibition largely correlated the antiviral activity.


Assuntos
Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Inibidores Enzimáticos/farmacologia , Ribonuclease H do Vírus da Imunodeficiência Humana/antagonistas & inibidores , Domínio Catalítico , Linhagem Celular , Técnicas de Química Sintética , Avaliação Pré-Clínica de Medicamentos/métodos , Inibidores Enzimáticos/química , Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/farmacologia , Humanos , Pirimidinonas/química , Ribonuclease H do Vírus da Imunodeficiência Humana/metabolismo , Relação Estrutura-Atividade
5.
J Med Chem ; 59(6): 2648-59, 2016 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-26927866

RESUMO

Human immunodeficiency virus (HIV) reverse transcriptase (RT) associated ribonuclease H (RNase H) remains an unvalidated antiviral target. A major challenge of specifically targeting HIV RNase H arises from the general lack of selectivity over RT polymerase (pol) and integrase (IN) strand transfer (ST) inhibitions. We report herein the synthesis and biochemical evaluations of three novel 3-hydroxypyrimidine-2,4-dione (HPD) subtypes carefully designed to achieve selective RNase H inhibition. Biochemical studies showed the two subtypes with an N-1 methyl group (9 and 10) inhibited RNase H in low micromolar range without significantly inhibiting RT polymerase, whereas the N-1 unsubstituted subtype 11 inhibited RNase H in submicromolar range and RT polymerase in low micromolar range. Subtype 11 also exhibited substantially reduced inhibition in the HIV-1 INST assay and no significant cytotoxicity in the cell viability assay, suggesting that it may be amenable to further structure-activity relationship (SAR) for identifying RNase H inhibitors with antiviral activity.


Assuntos
Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Transcriptase Reversa do HIV/antagonistas & inibidores , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/farmacologia , Ribonuclease H do Vírus da Imunodeficiência Humana/antagonistas & inibidores , Uracila/análogos & derivados , Domínio Catalítico/efeitos dos fármacos , RNA Polimerases Dirigidas por DNA/antagonistas & inibidores , Desenho de Fármacos , Transcriptase Reversa do HIV/efeitos dos fármacos , HIV-1/efeitos dos fármacos , Humanos , Modelos Moleculares , Reação em Cadeia da Polimerase , Relação Estrutura-Atividade , Uracila/síntese química , Uracila/farmacologia
6.
J Med Chem ; 59(13): 6136-48, 2016 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-27283261

RESUMO

Resistance selection by human immunodeficiency virus (HIV) toward known drug regimens necessitates the discovery of structurally novel antivirals with a distinct resistance profile. On the basis of our previously reported 3-hydroxypyrimidine-2,4-dione (HPD) core, we have designed and synthesized a new integrase strand transfer (INST) inhibitor type featuring a 5-N-benzylcarboxamide moiety. Significantly, the 6-alkylamino variant of this new chemotype consistently conferred low nanomolar inhibitory activity against HIV-1. Extended antiviral testing against a few raltegravir-resistant HIV-1 clones revealed a resistance profile similar to that of the second generation INST inhibitor (INSTI) dolutegravir. Although biochemical testing and molecular modeling also strongly corroborate the inhibition of INST as the antiviral mechanism of action, selected antiviral analogues also potently inhibited reverse transcriptase (RT) associated RNase H, implying potential dual target inhibition. In vitro ADME assays demonstrated that this novel chemotype possesses largely favorable physicochemical properties suitable for further development.


Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/farmacologia , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , Pirimidinonas/farmacologia , Ribonuclease H/antagonistas & inibidores , Linhagem Celular , Farmacorresistência Viral , Infecções por HIV/virologia , Integrase de HIV/metabolismo , Inibidores de Integrase de HIV/química , HIV-1/fisiologia , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Modelos Moleculares , Oxazinas , Piperazinas , Piridonas , Pirimidinonas/química , Raltegravir Potássico/farmacologia , Ribonuclease H/metabolismo
7.
ACS Med Chem Lett ; 6(1): 95-9, 2015 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-25589938

RESUMO

The Ser/Thr protein kinase, RSK, is associated with oncogenesis, and therefore, there are ongoing efforts to develop RSK inhibitors that are suitable for use in vivo. SL0101 is a natural product that demonstrates selectivity for RSK inhibition. However, SL0101 has a short biological half-life in vivo. To address this issue we designed a set of eight cyclitol analogues, which should be resistant to acid catalyzed anomeric bond hydrolysis. The analogues were synthesized and evaluated for their ability to selectively inhibit RSK in vitro and in cell-based assays. All the analogues were prepared using a stereodivergent palladium-catalyzed glycosylation/cyclitolization for installing the aglycon. The l-cyclitol analogues were found to inhibit RSK2 in in vitro kinase activity with a similar efficacy to that of SL0101, however, the analogues were not specific for RSK in cell-based assays. In contrast, the d-isomers showed no RSK inhibitory activity in in vitro kinase assay.

8.
Oncotarget ; 5(21): 10665-77, 2014 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-25359765

RESUMO

Histone lysine methylation regulates gene expression and cancer initiation. Bioinformatics analysis suggested that DOT1L, a histone H3-lysine79 (H3K79) methyltransferase, plays a potentially important role in breast cancer. DOT1L inhibition selectively inhibited proliferation, self-renewal, metastatic potential of breast cancer cells and induced cell differentiation. In addition, inhibitors of S-adenosylhomocysteine hydrolase (SAHH), such as neplanocin and 3-deazaneplanocin, also inhibited both H3K79 methylation and proliferation of breast cancer cells in vitro and in vivo. The activity of SAHH inhibitors was previously attributed to inhibition of H3K27 methyltransferase EZH2. However, inhibition of EZH2 by a specific inhibitor did not contribute to cell death. SAHH inhibitors had only weak activity against H3K27 methylation and their activity is therefore mainly due to DOT1L/H3K79 methylation inhibition. Overall, we showed that DOT1L is a potential drug target for breast cancer.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Metilação de DNA , Inibidores Enzimáticos/farmacologia , Histonas/química , Lisina , Metiltransferases/antagonistas & inibidores , Adenosina/análogos & derivados , Adenosina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Western Blotting , Neoplasias da Mama/genética , Ciclo Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Citometria de Fluxo , Histona-Lisina N-Metiltransferase , Histonas/genética , Histonas/metabolismo , Humanos , Técnicas Imunoenzimáticas , Metiltransferases/genética , Metiltransferases/metabolismo , Camundongos , Camundongos Nus , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Org Lett ; 16(22): 5996-9, 2014 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-25372628

RESUMO

In an effort to improve upon the in vivo half-life of the known ribosomal s6 kinase (RSK) inhibitor SL0101, C4″-amide/C6″-alkyl substituted analogues of SL0101 were synthesized and evaluated in cell-based assays. The analogues were prepared using a de novo asymmetric synthetic approach, which featured Pd-π-allylic catalyzed glycosylation for the introduction of a C4″-azido group. Surprisingly replacement of the C4″-acetate with a C4″-amide resulted in analogues that were no longer specific for RSK in cell-based assays.


Assuntos
Amidas/química , Benzopiranos/síntese química , Monossacarídeos/síntese química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Quinases S6 Ribossômicas 90-kDa/antagonistas & inibidores , Benzopiranos/química , Benzopiranos/farmacologia , Glicosilação , Meia-Vida , Estrutura Molecular , Monossacarídeos/química , Monossacarídeos/farmacologia , Proteínas Serina-Treonina Quinases/síntese química , Proteínas Serina-Treonina Quinases/química , Proteínas Serina-Treonina Quinases/farmacologia , Relação Estrutura-Atividade
10.
ACS Med Chem Lett ; 4(2): 175-179, 2012 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-23519677

RESUMO

Enhanced activity of the Ser/Thr protein kinase, RSK, is associated with transformation and metastasis, which suggests that RSK is an attractive drug target. The natural product, SL0101 (kaempferol 3-O-(3″,4″-di-O-acetyl-α-L-rhamnopyranoside), has been shown to be a RSK selective inhibitor. However, the Ki for SL0101 is 1 µM with a half-life of less than 30 min in vivo. To identify analogues with improved efficacy we designed a set of analogues based on the crystallographic model of SL0101 in complex with the RSK2 N-terminal kinase domain. We identified an analogue with a 5″-n-propyl group on the rhamnose that has > 40-fold improved affinity for RSK relative to SL0101 in an in vitro kinase assay. This analogue preferentially inhibited the proliferation of the human breast cancer line, MCF-7, versus the normal untransformed breast line, MCF-10A, which is consistent with results using SL0101. However, the efficacy of the 5″-n-propyl analogue to inhibit MCF-7 proliferation was only two-fold better than for SL0101, which we hypothesize is due to limited membrane permeability. The improved affinity of the 5″-n-propyl analogue for RSK will aid in the design of future compounds for in vivo use.

11.
ACS Med Chem Lett ; 3(12): 1086-1090, 2012 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-23543830

RESUMO

Two known cleistriosides and six known cleistetrosides were synthesized and evaluated for anticancer and antibacterial activity. This study, for the first time, reports anticancer activity and comprehensively the antibacterial activity for these oligosaccharide natural products. In addition, two new unnatural cleistetroside analogues were synthesized and tested. Biological activities for the ten oligosaccharides against B. subtilis were found to range between 4 and >64 µM, and for NCI-H460 human lung cancer epithelial cells between 7.5 and 90.9 µM. Similar activities were found for seven of the oligosaccharides against the NCI panel of 60 cell lines. The degree of acylation and location of the specific acetate groups had significant effects on the anticancer and antibacterial activity of both the cleistriosides and cleistetrosides.

12.
ACS Med Chem Lett ; 2(4): 259-263, 2011 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-21572583

RESUMO

A highly regio- and stereo-selective asymmetric synthesis of various C5'-alkyl side chains of rhamnosyl- and amicetosyl-digitoxigenin analogs has been established via palladium-catalyzed glycosylation with post-glycosylated dihydroxylation or diimide reduction. The C5'-methyl group in both α-l-rhamnose and α-l-amicetose digitoxin analogs displayed a steric directed apoptosis induction and tumor growth inhibition against non-small cell human lung cancer cells (NCI-H460). The anti-tumor activity is significantly reduced when the steric hindrance is increased at C5'-stereocenter.

13.
Org Lett ; 12(23): 5466-9, 2010 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-21038879

RESUMO

The de novo asymmetric syntheses of several partially acylated dodecanyl tri- and tetra-rhamnoside natural products (cleistriosides-5 and 6 and cleistetrosides-2 to 7) have been achieved (19-24 steps). The divergent route requires the use of three or less protecting groups. The asymmetry was derived via Noyori reduction of an acylfuran. The rhamno-stereochemistry was installed by a diastereoselective palladium-catalyzed glycosylation, ketone reduction and dihydroxylation.


Assuntos
Produtos Biológicos/síntese química , Glicosídeos Cardíacos/síntese química , Catálise , Glicosilação , Hidroxilação , Cetonas/química , Estrutura Molecular , Oxirredução , Paládio/química , Estereoisomerismo
14.
Org Lett ; 12(22): 5150-3, 2010 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-20958086

RESUMO

A divergent and highly stereoselective route to 11 glycosylated methymycin analogues has been developed. The key to the success of this method was the iterative use of the Pd-catalyzed glycosylation reaction and postglycosylation transformation. This unique application of Pd-catalyzed glycosylation demonstrates the breath of α/ß- and d/l-glycosylation of macrolides that can be efficiently prepared using a de novo asymmetric approach to the carbohydrate portion.


Assuntos
Antibacterianos/síntese química , Macrolídeos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Catálise , Técnicas de Química Combinatória , Glicosilação , Macrolídeos/química , Macrolídeos/farmacologia , Estrutura Molecular , Paládio/química , Estereoisomerismo , Streptomyces/química
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