RESUMO
The total synthesis of (+)-03219A, a rare Δ8,9-pregnene isolated from the marine-derived Streptomyces sp. SCSIO 03219, is described that is based on a series of transformations that enable progression from epichlorohydrin to an ent-estrane, then conversion to a nat-androstane, and finally establishment of the natural product target. Key to the success of these studies was implementation of two rearrangement processes to formally invert the quaternary center at C13 and establish the C10 quaternary center.
Assuntos
Androstanos/síntese química , Estranos/química , Pregnenos/síntese química , Streptomyces/química , Androstanos/química , Estrutura Molecular , Pregnenos/química , Streptomyces/isolamento & purificaçãoRESUMO
A reaction of copper(i) halides (X = I, Br, Cl) and silver(i) halides with 9-anthraldehyde thiosemicarbazone (9-Hanttsc, H1L) and triphenylphosphine produced halogen-bridged dinuclear complexes, [M2(µ2-X)2(η1-S-9-Hanttsc)2(Ph3P)2] (M = Cu, X = Cl, 1; Br, 2; I, 3; M = Ag, X = Cl, 4; Br, 5). A similar reaction of 9-anthraldehyde-N1-methyl thiosemicarbazone (9-Hanttsc-N1-Me, H2L) with Ph3P and silver(i) halides yielded sulfur-bridged dimers, [Ag2X2(µ2-S-9-Hanttsc-N1-Me)2(Ph3P)2] (X = Cl, 9; Br, 10), however with copper(i) halides insoluble compounds were formed, which upon the addition of one extra mole of Ph3P gave mononuclear complexes of the formula [CuX(η1-S-9-Hanttsc-N1-Me)(Ph3P)2] (X = Cl, 6; Br, 7; I, 8). All of the complexes have been characterized by elemental analysis, NMR (1H, 13C) spectroscopy and single crystal X-ray crystallography (2, 5, 6, and 9). Both the ligands (H1L and H2L) and their complexes (1-10) were tested for their anti-tubercular and anticancer activities. The interactions of the ligands and their complexes (copper and silver) with calf thymus DNA (ct-DNA) and human serum albumin (HSA) were examined through UV-visible and fluorescence spectroscopy. Results showed that copper complex 2 displayed strong interactions with ct-DNA and HSA having binding constant values of 6.66 × 104 M-1 and 3.28 × 104 M-1, respectively, followed by silver complex 10 which gave binding constant values of 4.60 × 104 M-1 and 3.06 × 104 M-1, respectively. All of the complexes also showed good interactions with DNA in docking studies.
Assuntos
Antineoplásicos/farmacologia , Antituberculosos/farmacologia , Complexos de Coordenação/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose Pulmonar/tratamento farmacológico , Antineoplásicos/síntese química , Antineoplásicos/química , Antituberculosos/síntese química , Antituberculosos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Cobre/química , Cobre/farmacologia , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Prata/química , Prata/farmacologia , Relação Estrutura-AtividadeRESUMO
Natural product and natural product-like molecules continue to be important for the development of pharmaceutical agents, as molecules in this class play a vital role in the pipeline for new therapeutics. Among these, tetracyclic terpenoids are privileged, with >100 being FDA-approved drugs. Despite this significant pharmaceutical success, there remain considerable limitations to broad medicinal exploitation of the class due to lingering scientific challenges associated with compound availability. Here, we report a concise asymmetric route to forging natural and unnatural (enantiomeric) C19 and C20 tetracyclic terpenoid skeletons suitable to drive medicinal exploration. While efforts have been focused on establishing the chemical science, early investigations reveal that the emerging chemical technology can deliver compositions of matter that are potent and selective agonists of the estrogen receptor beta, and that are selectively cytotoxic in two different glioblastoma cell lines (U251 and U87).
Assuntos
Neoplasias Encefálicas , Receptor beta de Estrogênio/agonistas , Glioblastoma , Terpenos/síntese química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Desenvolvimento de Medicamentos , Humanos , Células-Tronco Neurais/efeitos dos fármacos , Estereoisomerismo , Terpenos/farmacologiaRESUMO
A series of monomeric tetrahedral complexes of stoichiometry, [MX(HL)(Ph3P)2] (In case of Mâ¯=â¯Cu, H1L, Xâ¯=â¯I, 1; Br, 2; Cl, 3; H3L, Xâ¯=â¯I, 4; Br, 5; Cl, 6; H4L, Xâ¯=â¯I, 7; Br, 8; Cl, 9 and in case of Mâ¯=â¯Ag, H1L, Xâ¯=â¯Cl, 13; Br, 14; H2L, Xâ¯=â¯Cl, 15, Br 16; H3L, Xâ¯=â¯Cl, 17, Br, 18) were synthesized by the reaction of copper (I) or silver (I) halides with indole-3-thiosemicarbazone (H1L) or 5-methoxy indole-3-thiosemicarbazone (H2L) or 5-methoxy indole-N1-methyl-3-thiosemicarbazone (H3L), whereas dimers of stoichiometry, [Cu2(µ-X)2(η1-S-H2L)2(Ph3P)2] (Xâ¯=â¯I, 10; Br, 11; Cl, 12) were obtained by the reaction of copper (I) halides with indole-N1-methyl-3-thiosemicarbazone (HIntsc-N1-Me, H2L). The synthesized complexes were characterized using NMR (1H and 13C) and single crystal X-ray diffraction (H2L, 3, 7, 8, 10, 11 and 13) as well as elemental analysis. Anti- M. tuberculosis activity of ligands (H1L-H4L) and their metal complexes (1-18) were evaluated against M. tuberculosis H37RV strain ATCC 27294. It has been observed that there is unusual enhancement in anti TB activity of these ligands on complexation with copper (I) and silver (I). Molecular modelling studies in the active binding site are also giving complementary theoretical support for the experimental biological data acquired.
Assuntos
Antituberculosos/química , Complexos de Coordenação/química , Cobre/química , Indóis/química , Prata/química , Tiossemicarbazonas/química , Antituberculosos/síntese química , Antituberculosos/farmacologia , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Sítios de Ligação , Complexos de Coordenação/metabolismo , Cristalografia por Raios X , Dimerização , Enoil-(Proteína de Transporte de Acila) Redutase (NADH)/química , Enoil-(Proteína de Transporte de Acila) Redutase (NADH)/metabolismo , Testes de Sensibilidade Microbiana , Conformação Molecular , Simulação de Acoplamento Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/metabolismo , Estrutura Terciária de Proteína , Relação Estrutura-Atividade , Tiossemicarbazonas/síntese química , Tiossemicarbazonas/farmacologiaRESUMO
Alkoxide-directed metal-centered intermolecular [2+2+2] annulation is shown to chemo-, regio-, and stereoselectively engage two polyunsaturated substrate in productive cyclization chemistry. This annulation process is unique in the field, revealing that it is possible to selectively engage three of five π-systems residing in the coupling partners in initial [2+2+2] reaction, and demonstrating that one of the two remaining π-systems (the TMS-alkyne) can ultimately serve to simply generate a new metallacyclopentene of great potential value in additional metallacycle-mediated coupling chemistry.
RESUMO
In the title compound, C15H17N3OS, the dihedral angle between the mean planes of the 2-hy-droxy-napthyl ring system and the hydrazinecarbo-thio-amide group is 73.7â (3)°. In the crystal, weak O-Hâ¯S and C-Hâ¯O inter-actions and π-π stacking inter-actions involving one of the hy-droxy-napthyl rings with a centroid-centroid distance of 3.6648â (14)â Å are observed, forming infinite chains along [010]. In addition, N-Hâ¯S inter-actions occur.