RESUMO
Immunoglobulin replacement therapy is a life-saving treatment in patients with immunodeficiency and effective in the management of autoimmune disorders. Immunoglobulins are administered intravenously or subcutaneously, with the latter route reducing systemic reactions and providing an option for self-infusion, increasing patient convenience, while decreasing patient burden, healthcare utilization, and costs. A major limitation with subcutaneous administrations is the frequency of infusion due to limited volumes administrable into subcutaneous space, necessitating increased drug concentration, absorption, and dispersion. Increasing the concentration of immunoglobulins from 10 to 20% halves the required volume, but leads to higher dynamic viscosity, limiting infusion rate. Recombinant human hyaluronidase increases dispersion and absorption of immunoglobulins allowing administration of ≤ 600 mL per site, but does not change viscosity. Since the viscosity of fluids depends on temperature, we tested the feasibility of in-line warming of immunoglobulin formulations to physiological temperatures. In vitro analysis showed no negative impact of in-line warming to 38 °C on product quality. Subcutaneous infusion studies in pigs confirmed the feasibility of infusion rates of up to 7.5 mL/min with in-line warmed TAK-881, an immunoglobulin 20% facilitated with recombinant human hyaluronidase. In-line pressures were reduced compared with conventional immunoglobulin 20%, and local tolerance was not altered. Reduction of in-line pressures was more pronounced with thinner needle sets, indicating a potential benefit for patients. In summary, an in in-line warming device can circumvent the limitation of high viscosity, while product quality and local tolerance are maintained. The results of the presented studies warrant further testing in a phase 1 clinical study.
Assuntos
Hialuronoglucosaminidase , Síndromes de Imunodeficiência , Humanos , Animais , Suínos , Hialuronoglucosaminidase/efeitos adversos , Imunoglobulinas/efeitos adversos , Síndromes de Imunodeficiência/tratamento farmacológico , Infusões Subcutâneas , Injeções SubcutâneasRESUMO
A series of new Luotonin A derivatives with substituents at rings A and E was synthesized, together with some E-ring-unsubstituted derivatives. Subsequently, the compound library was examined in silico for their binding into a previously proposed site in the DNA/topoisomerase I binary complex. Whereas no convincing correlation between docking scores and biological data from in vitro assays could be found, one novel 4,9-diamino Luotonin A derivative had strong antiproliferative activity based on massive G2/M phase arrest. As this biological activity clearly differs from the reference compound Camptothecin, this strongly indicates that at least some Luotonin A derivatives may be potent antiproliferative agents, however with a different mode of action.
Assuntos
Antineoplásicos/farmacologia , Simulação de Acoplamento Molecular , Pirróis/farmacologia , Quinonas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Pirróis/síntese química , Pirróis/química , Quinonas/síntese química , Quinonas/química , Estereoisomerismo , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
Following two orthogonal synthetic routes, a series of all four possible A-ring amino derivatives of the natural product Luotonin A (a known Topoisomerase I inhibitor) was synthesized. In both strategies, intramolecular cycloaddition reactions are the key step. The target compounds were obtained in good yields by mild catalytic transfer hydrogenation of the corresponding nitro precursors. In-vitro evaluation of the antiproliferative activity towards human tumor cell lines revealed the 4-amino compound (5b) to be the most effective agent, showing an interesting profile of cytotoxic activity. Among other effects, a significant G2/M cell cycle arrest was observed for this compound, suggesting that either Topoisomerase I is not the only biological target, or that some atypical mechanism is responsible for inhibition of this enzyme.
Assuntos
Alcaloides/síntese química , Alcaloides/farmacologia , Pirróis/síntese química , Pirróis/farmacologia , Quinonas/síntese química , Quinonas/farmacologia , Alcaloides/química , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Química Sintética , Humanos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Pirróis/química , Quinonas/química , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-Atividade , Inibidores da Topoisomerase I/síntese química , Inibidores da Topoisomerase I/química , Inibidores da Topoisomerase I/farmacologiaRESUMO
An oxidative ring opening reaction of the central ring C in the alkaloid Luotonin A and two of its derivatives was found to occur upon heating with an excess amine and potassium carbonate in dimethylsulfoxide (DMSO) solution in the presence of air oxygen. The structure of the novel amide-type products was elucidated and a possible mechanism for this reaction is proposed. Four of the new compounds show moderate in vitro anticancer activity towards human colon adenocarcinoma cells.
Assuntos
Oxirredução , Pirróis/química , Quinonas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Humanos , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Estrutura Molecular , Pirróis/síntese química , Pirróis/farmacologia , Quinonas/síntese química , Quinonas/farmacologiaRESUMO
Weinreb amidation of ethyl 4-oxo-3,4-dihydroquinazoline-2-carboxylate with aromatic amines provides a significantly improved route to anilide-type key intermediates for the synthesis of the anticancer alkaloid, luotonin A, and new A-ring-modified derivatives thereof. This method has advantages concerning overall yield, brevity, and versatility with regard to the aromatic amine component, even if the latter has less favourable nucleophilicity, solubility and/or stability properties. This is demonstrated by the concise synthesis of a small library of luotonin A analogues, including a novel thiophene isostere of the alkaloid.
Assuntos
Pirróis/síntese química , Quinonas/síntese química , Descarboxilação , Hidrólise , Pirróis/química , Quinonas/químicaRESUMO
P-Glycoprotein (P-gp, ABCB1) plays a significant role in determining the ADMET properties of drugs and drug candidates. Substrates of P-gp are not only subject to multidrug resistance (MDR) in tumor therapy, they are also associated with poor pharmacokinetic profiles. In contrast, inhibitors of P-gp have been advocated as modulators of MDR. However, due to the polyspecificity of P-gp, knowledge on the molecular basis of ligand-transporter interaction is still poor, which renders the prediction of whether a compound is a P-gp substrate/non-substrate or an inhibitor/non-inhibitor quite challenging. In the present investigation, we used a set of fingerprints representing the presence/absence of various functional groups for machine learning based classification of a set of 484 substrates/non-substrates and a set of 1935 inhibitors/non-inhibitors. Best models were obtained using a combination of a wrapper subset evaluator (WSE) with random forest (RF), kappa nearest neighbor (kNN) and support vector machine (SVM), showing accuracies >70%. Best P-gp substrate models were further validated with three sets of external P-gp substrate sources, which include Drug Bank (n = 134), TP Search (n = 90) and a set compiled from literature (n = 76). Association rule analysis explores the various structural feature requirements for P-gp substrates and inhibitors.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Biologia Computacional , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Algoritmos , Bases de Dados de Produtos Farmacêuticos , Substituição de Medicamentos , Modelos Moleculares , Estrutura MolecularRESUMO
A series of novel 3-(indol-1-yl)prop-1-yn-1-yl-substituted phthalazines and related azines was prepared via a concise pathway by palladium-catalyzed cross-coupling of appropriate halo-azines and N-propargylindoles. Some of the compounds exhibited significant antitumor activity in an in-vitro assay.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Indóis/química , Indóis/farmacologia , Ftalazinas/química , Ftalazinas/farmacologia , Antineoplásicos/síntese química , Catálise , Indóis/síntese química , Paládio/química , Ftalazinas/síntese químicaRESUMO
Reaction of the title compound with hydrazine in the presence of air gives the 1-unsubstituted parent system via oxidative dehydrazination of the 1-hydrazino intermediate. The latter can be obtained in high yield by carrying out the hydrazinolysis step under inert gas, and it is smoothly converted into [1,2,4]-triazolo[4',3':1,6]pyridazino[4,5- b]indoles.
Assuntos
Hidrazinas/química , Indóis/química , Indóis/síntese química , Piridazinas/química , Linhagem Celular Tumoral , Inibidores do Crescimento/síntese química , Inibidores do Crescimento/química , Humanos , Oxigênio/químicaRESUMO
A series of b-fused carbazoles structurally related to pyrido[4,3-b]carbazole-type alkaloids was prepared, utilizing the Diels-Alder reaction of 1-methylpyrano[3,4-b]indol-3(9H)-one with electron-deficient acetylenic dienophiles as the key step. The title compound (14) thus obtained in only four steps represents a new 3-aza analog of the antitumor natural product, olivacine.