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1.
J Org Chem ; 86(23): 17184-17196, 2021 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-34786938

RESUMO

A visible light-mediated arylation protocol for t-amines has been reported through the coupling of γ- and α-amino alkyl radicals with different aryl diazonium salts using Ru(bpy)3Cl2·6H2O as a photocatalyst. Structurally different 9-aryl-9,10-dihydroacridine, 1-aryl tetrahydroisoquinoline, hexahydropyrrolo[2,1-a]isoquinoline, and hexahydro-2H-pyrido[2,1-a]isoquinoline frameworks with different substitution patterns have been synthesized in good yield using this methodology.

2.
Org Lett ; 23(20): 7730-7734, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34612036

RESUMO

Photocatalytic regiospecific p-silylation of arenes has been achieved by the coupling of in situ generated silyl radical with arene radical cation. The strategy involves reductive activation of PhSe-SiR3 and single electron transfer from the electron rich arene to 9,10-dimethoxyanthracene radical cation (DMA•+). p-Silyl arenes, thus formed, are further utilized for exclusive o-silylation reaction and for regiospecific o-acylation as well as o-alkylation reaction.

3.
Front Oncol ; 11: 710585, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34568037

RESUMO

Background: Treatment of malignant melanoma has undergone a paradigm shift with the advent of immune checkpoint inhibitors (ICI) and targeted therapies. However, access to ICI is limited in low-middle income countries (LMICs). Patients and Methods: Histologically confirmed malignant melanoma cases registered from 2013 to 2019 were analysed for pattern of care, safety, and efficacy of systemic therapies (ST). Results: There were 659 patients with a median age of 53 (range 44-63) years; 58.9% were males; 55.2% were mucosal melanomas. Most common primary sites were extremities (36.6%) and anorectum (31.4%). Nearly 10.8% of the metastatic cohort were BRAF mutated. Among 368 non-metastatic patients (172 prior treated, 185 de novo, and 11 unresectable), with a median follow-up of 26 months (0-83 months), median EFS and OS were 29.5 (95% CI: 22-40) and 33.3 (95% CI: 29.5-41.2) months, respectively. In the metastatic cohort, with a median follow up of 24 (0-85) months, the median EFS for BSC was 3.1 (95% CI 1.9-4.8) months versus 3.98 (95% CI 3.2-4.7) months with any ST (HR: 0.69, 95% CI: 0.52-0.92; P = 0.011). The median OS was 3.9 (95% CI 3.3-6.4) months for BSC alone versus 12.0 (95% CI 10.5-15.1) months in any ST (HR: 0.38, 95% CI: 0.28-0.50; P < 0.001). The disease control rate was 51.55%. Commonest grade 3-4 toxicity was anemia with chemotherapy (9.5%) and ICI (8.8%). In multivariate analysis, any ST received had a better prognostic impact in the metastatic cohort. Conclusions: Large real-world data reflects the treatment patterns adopted in LMIC for melanomas and poor access to expensive, standard of care therapies. Other systemic therapies provide meaningful clinical benefit and are worth exploring especially when the standard therapies are challenging to administer.

4.
Int J Pharm ; 608: 121063, 2021 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-34481007

RESUMO

Pharmaceutical cocrystals and salts are extensively researched in recent years due to their ability to tune the physicochemical properties of active pharmaceutical ingredients (APIs). A model API, olanzapine, an atypical antipsychotic drug classified as Biopharmaceutical Classification System class II, is used in this study. Cocrystals and salts of olanzapine are discovered using solvent drop grinding and ball milling. Appropriate coformers were selected based on a combination of hydrogen-bond propensity (HBP) and hydrogen-bond coordination (HBC) calculations. Eight new multicomponent phases of olanzapine, including one cocrystal hydrate with phenol; four anhydrous salts with salicylic acid, terephthalic acid, anthranilic acid, 3-hydroxybenzoic acid, and 2-aminoterephthalic acid; one salt dihydrate with terephthalic acid; and one salt solvate with 3-hydroxybenzoic acid and acetonitrile, have been discovered and characterized by PXRD and DSC. One reported cocrystal (olanzapine-resorcinol) has also been considered for the dissolution test. All these newly formed solid phases followed the "ΔpKa rule of 3". The crystal structures of cocrystal/salts were determined by single-crystal X-ray (sc-XRD) diffraction. With the collected single-crystal data, the crystal packings were found to be primarily stabilized via strong hydrogen bonds between carboxyl, phenolic hydroxyl of co-formers/salt-formers with the piperazine and diazepine nitrogen of olanzapine, which confirmed the predicted result from the HBP and HBC calculations. HPLC coupled with UV-vis detector was used in the solubility and dissolution test instead of UV-vis spectroscopy, to avoid the peak overlap between olanzapine and co-formers/salt-formers. A threefold increase in the solubility was observed in olanzapinium 3-hydroxybenzoate and olanzapinium anthranilate, and an almost fivefold increase in solubility of olanzapinium 2-aminoterephthalate.


Assuntos
Sais , Cristalização , Ligação de Hidrogênio , Olanzapina , Solubilidade
5.
Beilstein J Org Chem ; 17: 932-963, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33981366

RESUMO

Functionalized tetrahydropyran (THP) rings are important building blocks and ubiquitous scaffolds in many natural products and active pharmaceutical ingredients (API). Among various established methods, the Prins reaction has emerged as a powerful technique in the stereoselective synthesis of the tetrahydropyran skeleton with various substituents, and the strategy has further been successfully applied in the total synthesis of bioactive macrocycles and related natural products. In this context, hundreds of valuable contributions have already been made in this area, and the present review is intended to provide the systematic assortment of diverse Prins cyclization strategies, covering the literature reports of the last twenty years (from 2000 to 2019), with an aim to give an overview on exciting advancements in this area and designing new strategies for the total synthesis of related natural products.

6.
Dalton Trans ; 49(22): 7459-7466, 2020 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-32432588

RESUMO

An oxacalix[4]arene-Ce(iii) complex viz. L-Ce(III) has been introduced for the selective detection of As(v) and Cr(vi) oxyanions in aqueous medium. The binding mode of L-Ce(III) + AsO43-/CrO42- was completely investigated with fluorometric titration, time resolve fluorescent decay and FTIR analyses. Photoinduced electron transfer (PET) and chelation-enhanced fluorescence (CHEF) play an important role in the sensing of these oxyanions. The characteristic fluorescence of the L-Ce(III) complex has been quenched by AsO43- and CrO42- through cascading the ligating sites. Cyclic voltammetry (CV) experiments with various scan rates suggest that the electrochemical processes on the electrodes were controlled by diffusion. Both the analytes exhibit a lower limit of detection (LOD) below their standard EPA permissible limits. Moreover, the probe successfully detects the oxyanions in environmental real samples with excellent recovery ranging from 97 to 101%.


Assuntos
Arsênio/análise , Calixarenos/química , Cromo/análise , Complexos de Coordenação/química , Corantes Fluorescentes/química , Fenóis/química , Poluentes Químicos da Água/química , Água/química , Ânions/análise , Complexos de Coordenação/síntese química , Cristalografia por Raios X , Corantes Fluorescentes/síntese química , Modelos Moleculares , Estrutura Molecular
7.
Acta Crystallogr E Crystallogr Commun ; 75(Pt 8): 1084-1089, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31417770

RESUMO

This study is an investigation into the crystal structure of the biologically active drug mol-ecule riluzole [RZ, 6-(tri-fluoro-meth-oxy)-1,3-benzo-thia-zol-2-amine], C8H5F3N2OS, and its derivative, the riluzolium chloride salt [RZHCl, 2-amino-6-(tri-fluoro-meth-oxy)-1,3-benzo-thia-zol-3-ium chloride], C8H6F3N2OS+·Cl-. In spite of repeated efforts to crystallize the drug, its crystal structure has not been reported to date, hence the current study provides a method for obtaining crystals of both riluzole and its corresponding salt, riluzolium hydro-chloride. The salt was obtained by grinding HCl with the drug and crystallizing the obtained solid from di-chloro-methane. The crystals of riluzole were obtained in the presence of l-glutamic acid and d-glutamic acid in separate experiments. In the crystal structure of RZHCl, the -OCF3 moiety is perpendicular to the mol-ecular plane containing the riluzolium ion, as can be seen by the torsion angle of 107.4 (3)°. In the case of riluzole, the torsion angles of the four different mol-ecules in the asymmetric unit show that in three cases the tri-fluoro-meth-oxy group is perpendicular to the riluzole mol-ecular plane and only in one mol-ecule does the -OCF3 group lie in the same mol-ecular plane. The crystal structure of riluzole primarily consists of strong N-H⋯N hydrogen bonds along with weak C-H⋯F, C-H⋯S, F⋯F, C⋯C and C⋯S inter-actions, while that of its salt is stabilized by strong [N-H]+⋯Cl- and weak C-H⋯Cl-, N-H⋯S, C-H⋯F, C⋯C, S⋯N and S⋯Cl- inter-actions.

8.
Chem Commun (Camb) ; 55(65): 9689-9692, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31347622

RESUMO

A general and efficient method for heterocyclization involving benzylic C(sp3)-H functionalization enabled by visible light photoredox catalysis to access a wide range of structurally diverse oxygen as well as nitrogen heterocycles up to a gram scale is reported. The potential application of this new methodology is demonstrated by the total synthesis of (-)-codonopsinine and (+)-centrolobine. Herein it is proposed that selectfluor, unlike a fluorinating reagent, acts as an oxidative quencher and a hydrogen radical acceptor.

9.
J Org Chem ; 83(16): 9547-9552, 2018 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-30033732

RESUMO

A novel ortho/ bay annulation reaction of perylene bisimide (PBI) has been explored in a single step synthetic procedure using perylene bisimide 1 and 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) in the absence of any metal catalyst. The single crystal solid-state X-ray diffraction structure showed a distorted framework of DBU-fused PBI 2. Compound 2 exhibited intense near-infrared absorption up to 950 nm. Reversible protonation and deprotonation accompany drastic changes in the photophysical characteristics. Further, the reaction of perylene biscarboxyanhydride with DBU offered a caprolactam ring-substituted perylene bisimide 3.

10.
Chem Biol Drug Des ; 92(6): 1924-1932, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29923688

RESUMO

A series of methyl or ethyl 4-(substitutedphenyl/pyridyl)-6-methyl-2-oxo/thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (HPM) analogues 4a-g were synthesized and evaluated for larvicidal activity against Anopheles arabiensis. These newly synthesized compounds were characterized by spectral studies such as FT-IR, NMR (1 H and 13 C), LC-MS, and elemental analysis. The conformational features and supramolecular assembly of molecules 4a, 4b, and 4e were further analyzed from single crystal X-ray study. The larvicidal activity of these tetrahydropyrimidine pharmacophore series was analyzed based on their relative substituents. Among the synthesized HPM analogous from the series, compounds 4d and 4e both having electron withdrawing chlorine group on phenyl ring at the fourth position of the tetrahydropyrimidine pharmacophore exhibited the most promising larvicidal activity.


Assuntos
Anopheles/efeitos dos fármacos , Inseticidas/química , Pirimidinas/química , Animais , Anopheles/crescimento & desenvolvimento , Cristalografia por Raios X , Inseticidas/farmacologia , Larva/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Conformação Molecular , Pirimidinas/farmacologia , Espectroscopia de Infravermelho com Transformada de Fourier
11.
Acta Crystallogr B Struct Sci Cryst Eng Mater ; 73(Pt 5): 805-819, 2017 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-28980984

RESUMO

Strong hydrogen bonds play a significant role in crystal packing. In particular, the involvement of interactions involving fluorine in controlling the crystal packing requires appropriate attention, especially in the presence of other strong hydrogen bonds. In the present study, a detailed quantitative assessment has been performed of the nature, energetics and topological properties derived from the electron density in model compounds based on fluorinated benzamides (a total of 46 fluorine-substituted benzamides containing multiple fluorine atoms) in the solid state. The primary motivation in the design of such molecules is to enhance the acidity of the interacting H atoms in the presence of an increasing number of F atoms on the molecular scaffold, resulting in increased propensity towards the formation of intermolecular interactions involving organic fluorine. This exercise has resulted in the identification of new and frequently occurring supramolecular synthons involving F atoms in the packing of molecules in the solid state. The energetics associated with short and directional intermolecular Csp2-H...F-Csp2 interactions with significantly high electrostatic contributions is noteworthy, and the topological analysis reveals the bonding character of these ubiquitous interactions in crystal packing in addition to the presence of Csp2-F...F-Csp2 contacts.

12.
Chemistry ; 23(5): 1023-1027, 2017 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-27897338

RESUMO

The discovery of three polymorphs of N-(3,5-difluorophenyl)-2,4-difluorobenzamide, of which two exist as concomitant polymorphs, highlights the significance of short, linear C-H⋅⋅⋅F intermolecular interactions in the solid state. The formation of these polymorphs can be regulated by monitoring the scan rate in differential scanning calorimetry. The phases have been characterized structurally and the investigation of the mechanical properties depicts that Form 1 is stiffer and harder than Form 2 by 50 % and 33 %, respectively.

13.
Acta Crystallogr E Crystallogr Commun ; 72(Pt 9): 1335-1338, 2016 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-27920929

RESUMO

The title hydrate, C13H14N2O4·H2O, crystallizes with two formula units in the asymmetric unit (Z' = 2). The dihedral angles between the planes of the tetra-hydro-pyrimidine ring and the 4-hy-droxy-phenyl ring and ester group are 86.78 (4) and 6.81 (6)°, respectively, for one mol-ecule and 89.35 (4) and 3.02 (4)° for the other. In the crystal, the organic mol-ecules form a dimer, linked by a pair of N-H⋯O hydrogen bonds. The hydroxy groups of the organic mol-ecules donate O-H⋯O hydrogen bonds to water mol-ecules. Further, the hy-droxy group accepts N-H⋯O hydrogen bonds from amides whereas the water mol-ecules donate O-H⋯O hydrogen bonds to the both the amide and ester carbonyl groups. Other weak inter-actions, including C-H⋯O, C-H⋯π and π-π, further consolidate the packing, generating a three-dimensional network.

14.
Org Lett ; 18(8): 1752-5, 2016 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-27028314

RESUMO

A Lewis acid catalyzed Nazarov-type cyclization of arylvinylcarbinol has been developed for the asymmetric synthesis of carbotetracyclic core of merosesquiterpenes. The reaction works only in the presence of 2 mol % of Sn(OTf)2 and Bi(OTf)3 in dichloroethane under elevated temperature. The methodology offers the synthesis of a variety of enantioenriched arylvinylcarbinols from commercially available (3aR)-sclareolide 9 in six steps with an eventual concise total synthesis of marine sesquiterpene quinol, akaol A (1a).


Assuntos
Diterpenos/química , Ácidos de Lewis/química , Metanol/química , Sesquiterpenos/síntese química , Catálise , Metanol/análogos & derivados , Estrutura Molecular , Sesquiterpenos/química , Estereoisomerismo
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