RESUMO
A chemoinformatic method was developed to extract nonflat scaffolds embedded in natural products within the Dictionary of Natural Products (DNP). The cedrane scaffold was then chosen as an example of a nonflat scaffold that directs substituents in three-dimensional (3D) space. A cedrane scaffold that has three orthogonal handles to allow generation of 1D, 2D, and 3D libraries was synthesized on a large scale. These libraries would cover more than 50% of the natural diversity of natural products with an embedded cedrane scaffold. Synthesis of three focused natural product-like libraries based on the 3D cedrane scaffold was achieved. A phenotypic assay was used to test the biological profile of synthesized compounds against normal and Parkinson's patient-derived cells. The cytological profiles of the synthesized analogues based on the cedrane scaffold revealed that this 3D scaffold, prevalidated by nature, can interact with biological systems as it displayed various effects against normal and Parkinson's patient-derived cell lines.
Assuntos
Produtos Biológicos/química , Materiais Biomiméticos/química , Materiais Biomiméticos/síntese química , Desenho de Fármacos , Informática , Materiais Biomiméticos/farmacologia , Linhagem Celular , Técnicas de Química Sintética , Humanos , Modelos Moleculares , Conformação Molecular , FenótipoRESUMO
Mass-guided fractionation of the MeOH extract from a specimen of the Australian marine sponge Hyrtios sp. resulted in the isolation of two new tryptophan alkaloids, 6-oxofascaplysin (2), and secofascaplysic acid (3), in addition to the known metabolites fascaplysin (1) and reticulatate (4). The structures of all molecules were determined following NMR and MS data analysis. Structural ambiguities in 2 were addressed through comparison of experimental and DFT-generated theoretical NMR spectral values. Compounds 1-4 were evaluated for their cytotoxicity against a prostate cancer cell line (LNCaP) and were shown to display IC50 values ranging from 0.54 to 44.9 µM.
Assuntos
Alcaloides/farmacologia , Antineoplásicos/farmacologia , Poríferos/química , Triptofano/farmacologia , Alcaloides/química , Alcaloides/isolamento & purificação , Animais , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Austrália , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Estrutura Molecular , Teoria Quântica , Relação Estrutura-Atividade , Triptofano/química , Triptofano/isolamento & purificaçãoRESUMO
Chemical investigations of two specimens of Trikentrion flabelliforme collected from Australian waters have resulted in the identification of four new indole alkaloids, trikentramides A-D (9-12). The planar chemical structures for 9-12 were established following analysis of 1D/2D NMR and MS data. The relative configurations for 9-12 were determined following the comparison of (1)H NMR data with data previously reported for related natural products. The application of a quantum mechanical modeling method, density functional theory, confirmed the relative configurations and also validated the downfield carbon chemical shift observed for one of the quaternary carbons (C-5a) in the cyclopenta[g]indole series. The indole-2,3-dione motif present in trikentramides A-C is rare in nature, and this is the first report of these oxidized indole derivatives from a marine sponge.
Assuntos
Alcaloides Indólicos/isolamento & purificação , Poríferos/química , Animais , Austrália , Alcaloides Indólicos/química , Biologia Marinha , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , OxirreduçãoRESUMO
Bioassay-guided investigation of the cyanobacterium Anabaena compacta extracts afforded spumigin J (1) and the known thrombin inhibitor spumigin A (2). The absolute configuration of 1 was analyzed by advanced Marfey's methodology. Compounds 1 and 2 inhibited thrombin with EC(50) values of 4.9 and 2.1 µM, and 0.7 and 0.2 µM in the cathepsin B inhibitory assay, respectively. The MM-GBSA methodology predicted spumigin A with 2S-4-methylproline as the better thrombin inhibitor.
Assuntos
Anabaena/química , Água Doce/microbiologia , Trombina/antagonistas & inibidores , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Prolina/análogos & derivados , Prolina/químicaRESUMO
Schiff bases bearing phenyl and pyridyl groups were synthesized by condensation of appropriate amines with 2-hydroxynaphthaldehyde. These Schiff bases were obtained as colored crystalline solids. The proton NMR spectra of these compounds showed a doublet for the NH protons indicating a keto tautomer for these Schiff bases. The pyridyl-substituted Schiff bases containing hydroxyl moiety were found to show the most downfield shift for the NH protons in DMSO solvent, and this was rationalized due to the formation of a six- and five-membered ring using hydrogen bonds for these two compounds. Correspondingly, the olefinic proton of the Schiff bases is also found to be a doublet due to coupling to the amine proton. These Schiff bases exhibited thermochromic properties. Detailed NMR spectral analysis for both the phenyl- and pyridyl-substituted Schiff bases is presented.
Assuntos
Bases de Schiff/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Padrões de Referência , Bases de Schiff/síntese química , EstereoisomerismoRESUMO
An efficient formal synthesis of (+/-)-hyphodermins A and D, metabolites of Hyphoderma radula, has been completed in 12 and 11 steps, respectively. The tricyclic carbon skeleton of enone 6 was rapidly assembled from diester 11 via an alpha brominationn-elimination sequence followed by anhydride formation. Regioselective reduction of the lactone group of enone 6 with LiAlH(t-BuO) 3 gave lactol 15. Lactol 15 was converted in two steps to (+/-)-hyphodermin D, without the need for complex protection-deprotection strategies. Lactol 15 was converted in three steps to (+/-)-hyphodermin A, via the key step of epoxidation of an enone in the presence of a THP lactol. A combination of NMR and ab initio studies suggests that the structures of hyphodermin C and D should be interchanged.
Assuntos
Furanos/síntese química , Naftalenos/síntese química , Acetais/química , Furanos/química , Metilação , Modelos Moleculares , Estrutura Molecular , Naftalenos/químicaRESUMO
An efficient formal synthesis of hyphodermin B 1, a metabolite of Hyphoderma radula, has been completed in 15% overall yield. The tricyclic carbon skeleton 3 was rapidly assembled from a novel vinyl enone via a Diels-Alder reaction, followed by dehydrogenation and anhydride formation. Selective reduction of anhydride 3 with LiAlH(t-BuO)3 gave hyphodermin B 1 in 99% yield. The structure of hyphodermin B 1 was confirmed by X-ray crystallographic analysis. The anhydride 3, bearing a gamma-carbonyl group, displayed unexpected reactivity with the anhydride carbonyl closest to the gamma-ketone being the most electrophilic site. This was confirmed by HF/6-31G calculations. In the presence of base, 3 underwent a rearrangement to the novel lactone 16.
Assuntos
Furanos/síntese química , Cetonas/química , Naftalenos/síntese química , Polyporales/química , Cristalografia por Raios X , Furanos/química , Modelos Moleculares , Estrutura Molecular , Naftalenos/química , EstereoisomerismoRESUMO
The relationship between a natural product's biosynthetic enzyme and its therapeutic target is unknown. The concept of protein fold topologies, as a determining factor in recognition, has been developed through molecular modeling techniques. We have shown that biosynthetic enzymes and the therapeutic targets of three classes of natural products that inhibit protein kinases share a common protein fold topology (PFT) and cavity recognition points despite having different fold type classifications. The clinical agent flavopiridol would have been identified by this new approach.
Assuntos
Produtos Biológicos/biossíntese , Produtos Biológicos/farmacologia , Flavonoides/química , Modelos Moleculares , Piperidinas/química , Plantas Medicinais/enzimologia , Dobramento de Proteína , Proteínas/química , Produtos Biológicos/química , Estrutura Molecular , Conformação Proteica , Inibidores de Proteínas Quinases/metabolismoRESUMO
Cyclic peptides have been reported to bind to multiple, unrelated classes of receptor with high affinity. Owing to the robustness of amide bond chemistry, the ability to explore extensive chemical diversity by incorporation of unnatural and natural amino acids, and the ability to explore conformational diversity, through the incorporation of various constraints, arrays of cyclic peptides can be tailored to broadly sample chemical diversity. We describe the combination of a safety catch linker with a directed-sorted procedure for the synthesis of large arrays of diverse cyclic peptides for high-throughput screening.
Assuntos
Técnicas de Química Combinatória/métodos , Biblioteca de Peptídeos , Peptídeos Cíclicos/síntese química , Aminoácidos/química , Automação , Técnicas de Química Combinatória/instrumentação , Estrutura Molecular , Peptídeos Cíclicos/químicaRESUMO
[reaction: see text] Cyclic tetrapeptides are an intriguing class of natural products. To synthesize highly strained cyclic tetrapeptides we developed a macrocyclization strategy that involves the inclusion of 2-hydroxy-6-nitrobenzyl (HnB) group at the N-terminus and in the "middle" of the sequence. The N-terminal auxiliary performs a ring closure/ring contraction role, and the backbone auxiliary promotes cis amide bonds to facilitate the otherwise difficult ring contraction. Following this route, the all-L cyclic tetrapeptide cyclo-[Tyr-Arg-Phe-Ala] was successfully prepared.