CYP51: A Major Drug Target in the Cytochrome P450 Superfamily

The cytochrome P540 (CYP) superfamily currently includes about 9000 proteins forming more than 800 families. The enzymes catalyze monooxygenation of a vast array of compounds and play essentially two roles. They provide biodefense (detoxification of xenobiotics, antibiotic production) and participate in biosynthesis of important endogenous molecules, particularly steroids. Based on these two roles, sterol 14/*alpha*/-demethylases (CYP51) belong to the second group of P450s. The CYP51 family, however, is very special as its members preserve strict functional conservation in enzyme activity in all biological kingdoms. At amino acid identity across the kingdoms as low as 25-30%, they all catalyze essentially the same three-step reaction of oxidative removal of the 14/*alpha*/-methyl group from the lanostane frame. This reaction is the required step in sterol biosynthesis of pathogenic microbes. We have shown that specific inhibition of protozoan CYP51 can potentially provide treatment for human trypanosomiases. Three sets of CYP51 inhibitors tested in vitro and in trypanosomal cells in this study include azoles [best results being 50% cell growth inhibition at <1 and at 1.3 muM for Trypanosoma cruzi (TC) and Trypanosoma brucei (TB), respectively], non-azole compounds (50% TC cell growth inhibition at 5 microM) and substrate analogs of the 14/*alpha*/-demethylase reaction. 32-Methylene cyclopropyl lanost-7-enol exhibited selectivity toward TC with 50% cell growth inhibition at 3 microM.     

微波辅助下N1-乙氧基羰基甲基-5-氟尿嘧啶的绿色合成

在微波辐射下,以氯乙酸和乙醇为原料,合成氯乙酸乙酯,再以氯乙酸乙酯和5-氟尿嘧啶为原料合成了重要的医药中间体N1-乙氧基羰基甲基-5-氟尿嘧啶。通过改变溶剂、微波辐射功率、辐射时间、碱,确定了最佳的反应条件,并讨论了这些因素对反应的影响。在以水为溶剂、辐射功率250 W、辐射时间7 m in的最佳条件下,快速、绿色合成了N1-乙氧基羰基甲基-5-氟尿嘧啶,收率达90%,是一种绿色、简便、有效的合成新方法。产物结构经1H NMR,13C NMR和质谱确证。     

Inhibitors of inducible NO synthase expression: total synthesis of (S)-curvularin and its ring homologues

(S)-Curvularin and its 13-, 14-, and 16-membered lactone homologues were synthesized through a uniform strategy in which a Kochi oxidative decarboxylation and ring-closing metathesis reactions constitute the key processes. In the evaluation of the anti-inflammatory effects of the synthesized compounds in assays using cells stably transfected with a human iNOS promoter-luciferase reporter gene construct, the 14- and 16-membered homologues showed a slightly higher inhibitory effect towards iNOS promoter activity than curvularin itself. However, the larger ring homologues also exhibited higher cytotoxicity, manifest in downregulated eNOS promoter activity. In contrast, the di-O-acetyl and 4-chloro derivatives of (S)-curvularin showed higher inhibitory efficiency towards induction of the iNOS promoter and less negative effect on eNOS promoter activity than curvularin.     

Sila-haloperidol, a silicon analogue of the dopamine (D2) receptor antagonist haloperidol: synthesis, pharmacological properties, and metabolic fate

Haloperidol (1 a), a dopamine (D(2)) receptor antagonist, is in clinical use as an antipsychotic agent. Carbon/silicon exchange (sila-substitution) at the 4-position of the piperidine ring of 1 a (R(3)COH --> R(3)SiOH) leads to sila-haloperidol (1 b). Sila-haloperidol was synthesized in a new multistep synthesis, starting from tetramethoxysilane and taking advantage of the properties of the 2,4,6-trimethoxyphenyl unit as a unique protecting group for silicon. The pharmacological profiles of the C/Si analogues 1 a and 1 b were studied in competitive receptor binding assays at D(1)-D(5), sigma(1), and sigma(2) receptors. Sila-haloperidol (1 b) exhibits significantly different receptor subtype selectivities from haloperidol (1 a) at both receptor families. The C/Si analogues 1 a and 1 b were also studied for 1) their physicochemical properties (log D, pK(a), solubility in HBSS buffer (pH 7.4)), 2) their permeability in a human Caco-2 model, 3) their pharmacokinetic profiles in human and rat liver microsomes, and 4) their inhibition of the five major cytochrome P450 isoforms. In addition, the major in vitro metabolites of sila-haloperidol (1 b) in human liver microsomes were identified using mass-spectrometric techniques. Due to the special chemical properties of silicon, the metabolic fates of the C/Si analogues 1 a and 1 b are totally different.     

生物标志物在生物药临床研究中的应用及生物分析策略

中国生物药研发进入快车道,新药研发费用不断攀升,但并没有提高药物上市的成功率,因此亟需对药物研发模式进行转变。为了提高药物研发成功率,以生物标志物为核心的转化医学新药研发模式被普遍接受。本文综述了以生物标志物为核心的转化医学新药研发思路,生物标志物在生物药临床研究中的应用,生物标志物生物分析策略,生物标志物在生物药临床研究中的机遇与挑战。通过对标国际,寻找中国优势,从生物标志物为立足点的转化医学研发模式寻找机遇,中国可以尽早做成具有全球影响力的创新药。     

胃癌靶向治疗药物临床实验研究进展

以往针对进展期胃癌进行化疗常作为其最佳治疗选择,但传统化疗不良反应大,耐药率高,成为治疗难点。近年来,分子靶向药物具有可选择性杀伤肿瘤细胞、药物不良反应小等优点,成为临床研究热点。以受体酪氨酸激酶为靶点的靶向药物联合化疗药物治疗胃癌的多项临床试验证实联合疗法可带来生存效益,将是胃癌治疗的有效手段。本文就胃癌靶向治疗药物临床实验研究进展进行综述。     

Revisiting Platinum-Based Anticancer Drugs to Overcome Gliomas

Although there are many patients with brain tumors worldwide, there are numerous difficulties in overcoming brain tumors. Among brain tumors, glioblastoma, with a 5-year survival rate of 5.1%, is the most malignant. In addition to surgical operations, chemotherapy and radiotherapy are generally performed, but the patients have very limited options. Temozolomide is the most commonly prescribed drug for patients with glioblastoma. However, it is difficult to completely remove the tumor with this drug alone. Therefore, it is necessary to discuss the potential of anticancer drugs, other than temozolomide, against glioblastomas. Since the discovery of cisplatin, platinum-based drugs have become one of the leading chemotherapeutic drugs. Although many studies have reported the efficacy of platinum-based anticancer drugs against various carcinomas, studies on their effectiveness against brain tumors are insufficient. In this review, we elucidated the anticancer effects and advantages of platinum-based drugs used in brain tumors. In addition, the cases and limitations of the clinical application of platinum-based drugs are summarized. As a solution to overcome these obstacles, we emphasized the potential of a novel approach to increase the effectiveness of platinum-based drugs.     

Transcriptional Modulation of the Hippo Signaling Pathway by Drugs Used to Treat Bipolar Disorder and Schizophrenia

Recent reports suggest a link between positive regulation of the Hippo pathway with bipolar disorder (BD), and the Hippo pathway is known to interact with multiple other signaling pathways previously associated with BD and other psychiatric disorders. In this study, neuronal-like NT2 cells were treated with amisulpride (10 µM), aripiprazole (0.1 µM), clozapine (10 µM), lamotrigine (50 µM), lithium (2.5 mM), quetiapine (50 µM), risperidone (0.1 µM), valproate (0.5 mM), or vehicle control for 24 h. Genome-wide mRNA expression was quantified and analyzed using gene set enrichment analysis (GSEA), with genes belonging to Hippo, Wnt, Notch, TGF- β, and Hedgehog retrieved from the KEGG database. Five of the eight drugs downregulated the genes of the Hippo pathway and modulated several genes involved in the interacting pathways. We speculate that the regulation of these genes, especially by aripiprazole, clozapine, and quetiapine, results in a reduction of MAPK and NFκB pro-inflammatory signaling through modulation of Hippo, Wnt, and TGF-β pathways. We also employed connectivity map analysis to identify compounds that act on these pathways in a similar manner to the known psychiatric drugs. Thirty-six compounds were identified. The presence of antidepressants and antipsychotics validates our approach and reveals possible new targets for drug repurposing.