RESUMO
Brusatol, a quassinoid natural product, is effective against multiple diseases including hematologic malignancies, as we reported recently by targeting the PI3Kγ isoform, but toxicity limits its further development. Herein, we report the synthesis of a series of conjugates of brusatol with amino acids and short peptides at its enolic hydroxyl at C-3. A number of conjugates with smaller amino acids and peptides demonstrated activities comparable to brusatol. Through in vitro and in vivo evaluations, we identified UPB-26, a conjugate of brusatol with a L- ß-homoalanine, which exhibits good chemical stability at physiological pH's (SGF and SIF), moderate rate of conversion to brusatol in both human and rat plasmas, improved mouse liver microsomal stability, and most encouragingly, enhanced safety compared to brusatol in mice upon IP administration.
Assuntos
Aminobutiratos/farmacologia , Antineoplásicos/farmacologia , Quassinas/farmacologia , Aminobutiratos/síntese química , Aminobutiratos/metabolismo , Aminobutiratos/toxicidade , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Antineoplásicos/toxicidade , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Masculino , Camundongos Endogâmicos NOD , Camundongos SCID , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Quassinas/síntese química , Quassinas/metabolismo , Quassinas/toxicidade , Ratos , Relação Estrutura-AtividadeRESUMO
An advanced intermediate toward anti-cancer quassinoids has been synthesized using a quadruple diene-transmissive [4+2]-cycloaddition strategy. High convergence is achieved thanks to a regio- and stereoselective hetero-Diels-Alder reaction using a thione. The relative stereochemistry of the final Diels-Alder adduct was controlled by tethered substituents introduced via a highly syn- and gamma-selective vinylogous Mukaiyama aldol.
Assuntos
Dioxanos/química , Quassinas/síntese química , Ciclização , EstereoisomerismoRESUMO
[chemical reaction: see text]. An advanced intermediate to the highly oxygenated triterpene quassinoids was prepared in 14 steps from tetrahydrofuran. The key steps are three diene-transmissive Diels-Alder cycloadditions. Several features of this synthesis are noteworthy, including a successful Mitsunobu reaction on an allenylic alcohol, a rare [4 + 2] cycloaddition involving an enethiol ether dienophile, and complete control over all 10 chiral centers created.
Assuntos
Furanos/química , Quassinas/química , Quassinas/síntese química , Ciclização , Furanos/síntese química , Estrutura Molecular , OxirreduçãoRESUMO
Bruceantin (1), a classical quassinoid with the highest reported antimalarial activity among the quassinoids examined thus far, was selected as a natural product lead for the design of a series of A/B-ring analogs. A viable strategy for the synthesis of the series was developed. The functionalized A-ring and the C-15 ester moiety in bruceantin are incorporated in all designed compounds. The preliminary bioassay results will be discussed in detail.
Assuntos
Antimaláricos/química , Antimaláricos/farmacologia , Desenho de Fármacos , Quassinas/química , Quassinas/farmacologia , Animais , Antimaláricos/síntese química , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Testes de Sensibilidade Parasitária , Plasmodium falciparum/efeitos dos fármacos , Quassinas/síntese química , Relação Estrutura-AtividadeRESUMO
On the basis of a comparative analysis for stability in mouse serum between 15-O-acetylbruceolide and bruceolide 15-methyl carbonate, several 3,15-dialkyl carbonates of bruceolide were synthesized and their in vitro antimalarial activity was assessed. Methyl, ethyl, and isopropyl carbonates with pronounced in vitro activity were further evaluated for in vivo antimalarial potency. Both the methyl and ethyl carbonates significantly increased the life span of mice as compared with 3,15-di-O-accetylbruceolide and chloroquine.
Assuntos
Antimaláricos/síntese química , Plasmodium falciparum/efeitos dos fármacos , Quassinas/síntese química , Animais , Antimaláricos/farmacologia , Antimaláricos/toxicidade , Estabilidade de Medicamentos , Malária/tratamento farmacológico , Camundongos , Plasmodium berghei , Quassinas/farmacologia , Quassinas/toxicidade , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
Brusatol, a biologically active natural product, was modified in four distinct positions through the covalent attachment of a furoxan moiety, which acts as a nitric oxide (NO) donor. Forty derivatives were synthesized and evaluated for their inhibitory effects on excess NO biosynthesis in activated macrophages. Among them, compound 75 demonstrated inhibition (IC50 = 0.067 µM) comparable to that of brusatol but were less cytotoxic. More importantly, even at very low doses (2 µmol/kg/day), compound 75 also showed substantial inhibitory efficacy against chronic obstructive pulmonary disease (COPD)-like inflammation in the mouse model induced by cigarette smoke (CS) and lipopolysaccharide (LPS). Particularly, this compound was over 100-fold less toxic (LD50 > 3852 µmol/kg) than brusatol and could be a promising lead for further studies. Notably, the improved properties of this derivative are associated with its NO-releasing capability.
Assuntos
Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Desenho de Fármacos , Óxido Nítrico/biossíntese , Quassinas/síntese química , Quassinas/farmacologia , Animais , Anti-Inflamatórios/efeitos adversos , Anti-Inflamatórios/química , Técnicas de Química Sintética , Feminino , Lipopolissacarídeos/efeitos adversos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Oxidiazóis/química , Doença Pulmonar Obstrutiva Crônica/induzido quimicamente , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/metabolismo , Quassinas/efeitos adversos , Quassinas/química , Fumar/efeitos adversos , Relação Estrutura-AtividadeRESUMO
A concise synthesis of the AB rings of samaderine C (12 steps, 8 isolation steps, 7.8% overall yield), a quassinoid with antifeedant and insecticidal activity, is described. The development of the first general approach to the trans-1,2-diol A-ring motif in samaderine C and other quassinoids is a key feature. The trans-1,2-diol is crafted via stereoselective α-hydroxylation (of a silyl enol ether) and reduction, a strategy that has much potential for quassinoid synthesis.
Assuntos
Quassinas/síntese química , Hidroxilação , Estrutura Molecular , Casca de Planta/química , Quassinas/química , Simaroubaceae/química , EstereoisomerismoAssuntos
Imunossupressores/síntese química , Nitrocompostos/síntese química , Fotoquímica , Polienos/química , Pironas/síntese química , Quassinas/síntese química , Imunossupressores/química , Espectrometria de Massas , Estrutura Molecular , Nitrocompostos/química , Pironas/química , Quassinas/químicaRESUMO
The reactivity of two new bicyclic cyclohexenones (13 and 27) with several Nazarov reagents is presented. A flexible synthetic strategy is developed and provides access to highly substituted tricycles related to quassinoids and triterpenes.
Assuntos
Cicloexanonas/química , Quassinas/síntese química , Triterpenos/síntese química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Catálise , Ciclização , Estrutura Molecular , Quassinas/química , Triterpenos/químicaRESUMO
First total syntheses of unnatural (-)-14-epi-samaderine E (5) and natural (-)-samaderine Y (2) were accomplished from (S)-(+)-carvone (6) in 18 and 21 steps, respectively. The syntheses are short, efficient (with an average yield of 80 % plus for each transformation), enantiospecific, and produce nine new chiral centers. The crucial points of the syntheses included a regioselective allylic oxidation on ring C, regio- and stereoselective reduction of ketone, a stereocontrolled epoxidation, an epoxymethano-bridge formation, a chemoselective Grignard reaction, an intramolecular Diels-Alder reaction, an intramolecular aldol addition, and a newly developed manganese(III)-catalyzed allylic oxidation on ring A.
Assuntos
Alcaloides/síntese química , Antineoplásicos Fitogênicos/síntese química , Monoterpenos/química , Quassinas/síntese química , Compostos Alílicos/química , Catálise , Ciclização , Monoterpenos Cicloexânicos , Modelos Moleculares , Oxirredução , EstereoisomerismoRESUMO
An advanced pentacyclic intermediate, amenable to further elaboration into the target molecules simalikalactone D and quassimarin, has been synthesized from (S)-(+)-carvone in 21 steps and with an overall yield of 12 %. The synthesis is efficient, stereocontrolled, enantiospecific, and chirality productive, creating eight new chiral centres in pentacycle, and should provide opportunities for rapid access to simalikalactone D analogues and other bioactive quassinoids. The reaction sequence involves a regioselective bishydroxylmethylation, a stereocontrolled epoxidation, an epoxymethano-bridge formation, a 1,3-sigmatropic rearrangement and an intramolecular Diels-Alder reaction as the key steps.
Assuntos
Antineoplásicos/química , Quassinas/química , Quassinas/síntese química , Antineoplásicos/síntese química , Cristalografia por Raios X , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/química , Estrutura MolecularRESUMO
A new C(19)-quassinoid-type glycoside has been isolated from the roots of Eurycoma longifolia. The structure elucidation of the compound was achieved by a combination of one- and two-dimensional NMR techniques, including (1)H-(1)H-correlation spectroscopy (COSY), (1)H-(13)C-heteronuclear correlation spectroscopy (HMQC), and (1)H-(13)C-heteronuclear multiple-bond correlation spectroscopy (HMBC), as well as high resolution electrospray ionization Fourier transformation mass spectrometry (HR-ESI-FT-MS) data. The C(1)-glycosidation site in the quassinoid framework is encountered for the first time.