Synthesis of cyclic tryptathionine peptides

The helicity of the tryptathionine moiety of the phallotoxins has been recognized by comparison with cyclic tryptathionine tripeptides. In order to investigate the influence of the configuration of the component amino acids on the conformation of the cyclic peptides, six analogue thioether tripeptides containing L- and D-alanine and L- and D-cysteine, respectively, have been synthesized. The CD spectra of the peptides are very similar to each other, showing mirror images of the CD of phalloidin and, therefore, negative helicity. The spectra of the D-cysteine containing compounds differ from the L-cysteine containing compounds by their weakly positive ellipticity values around 270 nm. The cyclization reaction of Boc-Hpi-D-Ala-D-Cys(STrt)OCH₃, along with the cyclic tripeptide, afforded a cyclic hexapeptide by dimerization. The CD spectrum of the dimer is very similar to that of phalloidin, thus pointing to a positive helicity of its two tryptathionine moieties. The dimeric thioether peptide forms a rather strong complex with Cu²⁺ ions.     

3-氯-4-氟苯胺亚甲基丙二酸二乙酯在惰性高沸点溶剂中的环化反应

用 ~1HNMR 方法测定了3-氯-4-氟苯胺亚甲基丙二酸二乙酯在二苯醚或石蜡油中加热环化所得产物中2与3的比例,结果表明此比例随着溶剂的不同而稍有变化,并且副产物3的组份随着溶剂用量增大而减少。     

5-氯吲哚酮的合成

目的 优化5--氯吲哚酮合成工艺，提高其收率。方法 以对氯苯胺为起始原料，与水合氯醛及盐酸羟胺反应生成对氯异亚硝基乙酰苯胺，然后在浓硫酸作用下经环合、水解得到5—氯靛红，再经Wolff—Kishner—黄鸣龙反应得到5—氯吲哚酮。结果与结论 总收率可达71％。本法具有原料价廉易得，反应条件温和，操作简便，收率高等优点。     

Synthetic peptide derived from α‐fetoprotein inhibits growth of human breast cancer: investigation of the pharmacophore and synthesis optimization

Abstract: A synthetic peptide that inhibits the growth of estrogen receptor positive (ER+) human breast cancers, growing as xenografts in mice, has been reported. The cyclic 9‐mer peptide, cyclo[EMTOVNOGQ], is derived from α‐fetoprotein (AFP), a safe, naturally occurring human protein produced during pregnancy, which itself has anti‐estrogenic and anti‐breast cancer activity. To determine the pharmacophore of the peptide, a series of analogs was prepared using solid‐phase peptide synthesis. Analogs were screened in a 1‐day bioassay, which assessed their ability to inhibit the estrogen‐stimulated growth of uterus in immature mice. Deletion of glutamic acid, Glu1, abolished activity of the peptide, but glutamine (Gln) or asparagine (Asn) could be substituted for Glu1 without loss of activity. Methionine (Met2) was replaced with lysine (Lys) or tyrosine (Tyr) with retention of activity. Substitution of Lys for Met2 in the cyclic molecule resulted in a compound with activity comparable with the Met2‐containing cyclic molecule, but with a greater than twofold increase in purity and corresponding increase in yield. This Lys analog demonstrated anti‐breast cancer activity equivalent to that of the original Met‐containing peptide. Therefore, Met2 is not essential for biologic activity and substitution of Lys is synthetically advantageous. Threonine (Thr3) is a nonessential site, and can be substituted with serine (Ser), valine (Val), or alanine (Ala) without significant loss of activity. Hydroxyproline (Hyp), substituted in place of the naturally occurring prolines (Pro4, Pro7), allowed retention of activity and increased stability of the peptide during storage. Replacement of the first Pro (Pro4) with Ser maintains the activity of the peptide, but substitution of Ser for the second Pro (Pro7) abolishes the activity of the peptide. This suggests that the imino acid at residue 7 is important for conformation of the peptide, and the backbone atoms are part of the pharmacophore, but Pro4 is not essential. Valine (Val5) can be substituted only with branched‐chain amino acids (isoleucine, leucine or Thr); replacement by d ‐valine or Ala resulted in loss of biologic activity. Thus, for this site, the bulky branched side chain is essential. Asparagine (Asn6) is essential for activity. Substitution with Gln or aspartic acid (Asp), resulted in reduction of biologic activity. Removal of glycine (Gly8) resulted in a loss of activity but nonconservative substitutions can be made at this site without a loss of activity indicating that it is not part of the pharmacophore. Cyclization of the peptide is facilitated by addition of Gln9, but this residue does not occur in AFP nor is it necessary for activity. Gln9 can be replaced with Asn, resulting in a molecule with similar activity. These data indicate that the pharmacophore of the peptide includes side chains of Val5 and Asn6 and backbone atoms contributed by Thr3, Val5, Asn6, Hyp7 and Gly8. Met2 and Gln9 can be modified or replaced. Glu1 can be replaced with charged amino acids, and is not likely to be part of the binding site of the peptide. The results of this study provide information that will be helpful in the rational modification of cyclo[EMTOVNOGQ] to yield peptide analogs and peptidomimetics with advantages in synthesis, pharmacologic properties, and biologic activity.     

二氢黄酮类化合物的合成研究进展

综述二氢黄酮类化合物的合成研究进展,总结已报道的各种类型的二氢黄酮合成方法,为二氢黄酮类新药研发提供方法学支持。合成方法包括:查尔酮环合、Friedel-Crafts反应、Knoevenagel缩合和Hoesch单酰基化反应,以及二氢黄酮的不对称合成,并简要介绍无溶剂合成二氢黄酮等"绿色"化学方法。     

Mechanistic studies on the drug metabolism and toxicity originating from cytochromes P450

Abstract

Cytochromes P450 are oxidizing enzymes; a few families of cytochromes P450 are implicated in drug metabolism. These enzymatic reactions involve many processes including (i) prodrug to drug conversion, (ii) easy excretion of drug, (iii) generation of reactive metabolites, many of which cause toxicity. In this review, the fundamental biochemical mechanisms associated with the conversion of drugs into the useful or toxic metabolites have been discussed. The mechanisms can be established with the help of many experimental methods like mass spectral analysis, NMR and in vitro analysis etc. Computational methods provide detailed atomic level information, which is generally not available from experimental studies. Thus, the in silico efforts in elucidating the molecular mechanisms are complementary to the known experimental methods and are often clearer (especially in providing 3D information about the metabolites and their reactions). Quantum chemical methods and molecular docking become especially very useful. This review includes five case studies, which explain how the atomic level details were obtained to explore the reaction mechanisms of drug metabolism by cytochromes P450.     

CuBr2/O2促进N-芳基-β-烯胺酯分子内氧化环合反应构建2,3-二取代吲哚

吲哚类化合物作为一类具有广泛生物和药理活性的有机分子,其合成研究具有重要的价值。而通过N-芳基烯胺的分子内氧化偶联反应构建吲哚类化合物成为合成吲哚类化合物最直接、高效的方法之一,得到合成化学家的广泛关注。基于此,本文发展以便宜的二价铜盐(CuBr2)、绿色氧化剂(O2)和吡啶作为配体共同促进的N-芳基-β-烯胺酯的分子内氧化环合反应,以58%~94%的收率成功地合成一系列2,3-二取代的吲哚类化合物,并对其进行核磁共振氢谱和碳谱表征。该合成策略为吲哚类化合物的合成提供了新的方法。     

Structure and function of cis‐acting RNA elements of flavivirus

The genus Flavivirus is a group of single‐stranded, positive‐sense RNA viruses that includes numerous human pathogens with global impact, such as dengue virus (DENV), yellow fever virus (YFV), West Nile virus (WNV), and Zika virus (ZIKV). The approximately 11‐kilobase genome is flanked by highly structured untranslated regions (UTRs), which contain various cis‐acting RNA elements with unique structures and functions. Moreover, local RNA elements circularize the genome non‐covalently through long‐range interactions. Interestingly, many flavivirus cis‐acting RNA elements contain group‐specific motifs or are specific for the given phylogenetic groups, suggesting their potential association with flavivirus evolution and diversification. In this review, we summarize recent advances about the structure and function of cis‐acting RNA elements in flavivirus genomes and highlight the potential implications for flavivirus evolution. Finally, the scientific questions remained to be answered in the field are also discussed.     

A gold mine for drug discovery: Strategies to develop cyclic peptides into therapies

As a versatile therapeutic modality, peptides attract much attention because of their great binding affinity, low toxicity, and the capability of targeting traditionally “undruggable” protein surfaces. However, the deficiency of cell permeability and metabolic stability always limits the success of in vitro bioactive peptides as drug candidates. Peptide macrocyclization is one of the most established strategies to overcome these limitations. Over the past decades, more than 40 cyclic peptide drugs have been clinically approved, the vast majority of which are derived from natural products. The de novo discovered cyclic peptides on the basis of rational design and in vitro evolution, have also enabled the binding with targets for which nature provides no solutions. The current review summarizes different classes of cyclic peptides with diverse biological activities, and presents an overview of various approaches to develop cyclic peptide-based drug candidates, drawing upon series of examples to illustrate each strategy.     

5,6—二甲基苯并咪唑的合成

以邻二甲苯为原料经乙酰化、肟化、重排、硝化、还原、环化合成５,６－二甲基苯并咪唑,总收率达４０％。