Metabolism-based drug design and drug targeting

Even at the early stages of drug discovery and structure-based drug design, the pharmacokinetic, pharmacodynamic and toxicological consequences of drug metabolism cannot be ignored. Drug metabolism is also of interest to medicinal chemists in the design of drugs with controlled, predictable deactivation after achieving the therapeutic objective in prodrug design and in chemical–enzymatic drug targeting. In this review, the authors provide an overview of concepts that can be utilized from drug discovery to pharmaceutical development to overcome problems associated with drug metabolism, or that may be used to take advantage of ‘designed-in’ metabolic activation to achieve drug targeting.     

Protein-protein interaction inhibitors: advances in anticancer drug design

ABSTRACT

Introduction: Pocket-based drug design has contributed to major scientific breakthroughs in pharmaceutical research and development (R&D). The integrated use of experimental and computational methods, primarily during the early phases of drug discovery, has enabled the development of highly potent and selective small-molecule ligands. In this scenario, the targeting of protein-protein interactions (PPIs) has emerged as an attractive strategy for designing innovative drugs for highly complex diseases, such as cancer.

Areas covered: This article focuses on the use of experimental and computational approaches with a diversity of PPI classes and discusses the relevant advances in the field, primarily for oncological applications. Analyses of the target binding pockets and medicinal chemistry approaches used to develop promising PPI inhibitors are provided, with an emphasis on data reported over the past 2 years.

Expert opinion: PPI drug discovery is a challenging field that depends completely on accurate structural data. The integration of molecular docking, nuclear magnetic resonance and X-ray crystallography is a cornerstone for the current development of effective PPI inhibitors. Although this field has not reached its peak, several compounds have entered clinical trials over the past few years, providing promising perspectives for novel therapies for highly prevalent and life-threatening conditions.     

Cyclopentenone: a special moiety for anticancer drug design

The conjugate cyclopent-en-one chemical group is a special moiety for anticancer drugs. Studies on cyclopentenone prostaglandins, clavulones and other compounds have revealed its mechanism of action and a wide spectrum of intracellular targets, ranging from nuclear factors to mitochondria. The introduction of the cyclopentenone moiety into molecules, such as jasmonates and chalcones, has been shown to boost their anticancer potential. In this work, reviewing pertinent up-to-date literature, we have pointed out potentially effective cyclopentenone-bearing compounds for anticancer clinical research and inspiring relationships for future drug design. In particular, it appears that the addition of cyclopentenone groups to target-orienting molecules, in order to inactivate specific proteins in cells, could be a helpful general strategy for the development of novel therapeutic molecules.     

Emerging roles of carbohydrates and glycomimetics in anticancer drug design

Tumorigenesis is accompanied by marked changes in the expression and presentation of various macromolecules at the cell surface. These tumor-associated adjustments result from the differential expression of genes coding for the production or post-translational modifications of these macromolecules during transformation to a particular tumor phenotype. In turn, tumor cells acquire distinct biophysical properties which set them apart from their normal counterparts. Alterations of carbohydrate structures and their organization on the surface of neoplastic cells is a hallmark of the tumorigenic and, most notably, the metastatic phenotype. Carbohydrate-protein and carbohydrate-carbohydrate interactions are critical events in the progression, dissemination and invasion of cancer cells. Many cell-cell contacts and subsequent remodeling of the tumor microenvironment are mediated by cell-surface glycans. The discovery of agents that modulate these interactions or interfere with the processing of tumor associated oligosaccharides is a fervent area of research today. This review will highlight the current status of the use of carbohydrate-based compounds that are being evaluated as potential anticancer therapeutics. In addition, the use of structures based on glycopeptides and carbohydrate mimetics will also be discussed.     

A novel valproic acid prodrug as an anticancer agent that enhances doxorubicin anticancer activity and protects normal cells against its toxicity in vitro and in vivo

The poor survival of patients with malignant gliomas, underscores the need to develop effective treatment modalities for this devastating disease. Epigenetic agents used in combination with chemotherapy provide a promising approach to evoke synergistic cytotoxicity in glioblastomas. Previously we have described the cytotoxic synergy between a butyric acid prodrug and radiation in glioblastoma cell lines and the potentiation of radiation efficacy in glioma xenografts. Herein, we describe and compare the activities of AN446 (valproyl ester-valpramide of acyclovir) a novel histone deacetylase inhibitor (HDACI) to the previously described AN7 a HDACI prodrug of butyric acid. In various cancer cell lines, AN446 was a ∼2–5-fold more potent anticancer agent HDACI than AN7. While AN446 augmented the anticancer efficacy of doxorubicin (Dox) it also reduced the Dox toxicity in non-cancerous cells. The interaction between AN446 and Dox in U251 and in 4T1 cell lines was synergistic in inducing cytotoxicity. We examined the concomitant physical and molecular changes in the tumor and heart of glioblastoma xenografts treated with AN446, AN7, Dox and the combination of the prodrugs with Dox. A weekly dose of 4 mg/kg Dox, caused toxicity in mice whereas AN446 (25 mg/kg) or AN7 (50 mg/kg) administered thrice weekly, did not. When Dox was administered with AN446 or AN7, the prodrugs ameliorated the decline in body weight, prolonged the time to failure and increased anticancer efficacy. Thus, the combination of Dox with AN446 or AN7 could add safety and efficacy to future treatment protocols for treating glioblastoma and other cancers.     

Potassium channels are a new target field in anticancer drug design

Potassium channels constitute a large and heterogeneous family with more than eighty genes which encode membrane proteins that control membrane potential. In addition to nerve and cardiac action potential, these proteins are involved in a number of physiological processes including volume regulation, apoptosis, immunomodulation and differentiation. Many potassium channels have been related to proliferation and cell-cycle progression in mammalian cell lines and certain potassium channels show impaired expression in cancer cells and tumours. In addition, in some cases a correlation has been established between the protein expression levels and the grade of malignancy of the tumour. Many drugs have been found to inhibit both K+ channel activity and cell-cycle progression. Since potassium channels may play a pivotal role in tumour cell proliferation, these proteins should be taken into account when designing new cancer treatment strategies. The increasing list of recent patents, covered in this review, shows the relevance of this emergent subject.     

Unanticipated acyloxymethylation of sumatriptan indole nitrogen atom and its implications in prodrug design

Sumatriptan is a potent and selective 5-HT(1B) and 5-HT(1D )agonist used in the symptomatic treatment of migraine; it shows poor oral bioavailability ascribed, in part, to its low lipophilicity. In an attempt to develop acyloxymethyl prodrugs of sumatriptan suitable for oral administration, we carried out the reaction of sumatriptan with chloromethyl esters. To our surprise, acyloxymethylation occurred preferentially at the indole nitrogen rather than at sulfonamide nitrogen, reflecting a difference either in product stability or in the nucleophilicities of the indole and sulfonamide anions. The hydrolysis of the corresponding N(1)-acyloxymethyl derivatives was studied in aqueous buffers and in human plasma, by HPLC. N(1)-Acyloxymethyl derivatives of sumatriptan are rapidly hydrolysed to the chemically stable N(1)-hydroxymethylsumatriptan at pH 1-13. Slow formation of the parent drug was observed only at high pH values. Hydrolysis of sumatriptan derivatives is slower in human plasma than in phosphate buffer and also generates N(1)-hydroxymethylsumatriptan rather than the parent drug. These results indicate that N(1)-acyloxymethyl derivatives of sumatriptan cannot be considered as true prodrugs of sumatriptan.     

Rational drug design of indazole‐based diarylurea derivatives as anticancer agents

A series of novel indazole‐based diarylurea derivatives targeting c‐kit were designed by structure‐based drug design. The derivatives were prepared, and their antiproliferative activities were evaluated against human colon cancer HCT‐116 cell line and hepatocellular carcinoma PLC/PRF/5 cell line. The antiproliferative activities demonstrated that six of nine compounds exhibited comparable activities with sorafenib against HCT‐116. The structure–activity relationship (SAR) analysis indicated that the indazole ring part tolerated different kinds of substituents, and the N position of the central pyridine ring played key roles in antiproliferative activity. The SAR and interaction mechanisms were further explored using molecular docking method. Compound 1i with N‐(2‐(pyrrolidin‐1‐yl)ethyl)‐carboxamide possessed improved solubility, 596.1 ng/ml and best activities, IC₅₀ at 1.0 μm against HCT‐116, and 3.48 μm against PLC/PRF/5. It is a promising anticancer agent for further development.     

Combinatorial approaches in anticancer drug discovery: recent advances in design and synthesis

Combinatorial technology for the generation of molecular diversity has evolved as an integrated component in accelerated drug discovery process. During the emerging days of combinatorial chemistry, solid-phase organic synthesis has been the leading strategy for the production of large libraries for lead discovery. As combinatorial techniques for the library synthesis has evolved, solution-phase synthesis of smaller, targeted libraries is gaining attention. Numerous syntheses of biologically active chemical libraries of small molecules have been reported during the past decade. This review will focus only on the recent literature of chemical libraries targeted towards anticancer properties. The synthesis, chemistry and biological activity of these libraries as anticancer agents are summarized.     

Cannabidiol as potential anticancer drug

Over the past years, several lines of evidence support an antitumourigenic effect of cannabinoids including Δ⁹-tetrahydrocannabinol (Δ⁹-THC), synthetic agonists, endocannabinoids and endocannabinoid transport or degradation inhibitors. Indeed, cannabinoids possess anti-proliferative and pro-apoptotic effects and they are known to interfere with tumour neovascularization, cancer cell migration, adhesion, invasion and metastasization. However, the clinical use of Δ⁹-THC and additional cannabinoid agonists is often limited by their unwanted psychoactive side effects, and for this reason interest in non-psychoactive cannabinoid compounds with structural affinity for Δ⁹-THC, such as cannabidiol (CBD), has substantially increased in recent years. The present review will focus on the efficacy of CBD in the modulation of different steps of tumourigenesis in several types of cancer and highlights the importance of exploring CBD/CBD analogues as alternative therapeutic agents.     

抗癌药物多烯紫杉醇的合成

目的 建立一种简便、经济的合成多烯紫杉醇的方法.方法 以反式-肉桂酸乙酯为原料,经不对称双羟化、环氧化、重氮化及氢化4步反应得到多烯紫杉醇手性C13侧链,再与保护的10-去乙酰巴卡亭Ⅲ对接、去保护得到多烯紫杉醇.结果 多烯紫杉醇手性C13侧链的4步反应总收率为76%,光学产率为99%,对接及去保护3步反应总收率为64%.结论 在多烯紫杉醇手性C13侧链的合成过程中,对价格昂贵的金鸡纳生物碱衍生物配体进行了回收和再利用,大大降低了反应成本.同时还优化了反应过程,避免了柱色谱分离,有利于多烯紫杉醇的工业化生产.     

抗癌药雷替曲塞的合成

目的研究抗癌药雷替曲塞的合成。方法以2-噻吩甲醛为起始原料,经硝化、氧化、酯化、还原、氨基保护、N-甲基化、水解、缩合、脱保护、N-烷基化、水解11步反应合成雷替曲塞。结果与结论总收率为12.9%,其结构经核磁共振氢谱、质谱确证。     

A theoretical study on interactions between mitoxantrone as an anticancer drug and DNA: application in drug design

This research is an effort to further understand the physicochemical interaction between the novel drug, mitoxantrone (MTX) and its biologic receptor, DNA. The ultimate goal is to design drugs that interact more with DNA. Understanding the physicochemical properties of the drug as well as the mechanism by which it interacts with DNA, it should ultimately allow the rational design of novel anti-cancer or anti-viral drugs. Molecular modelling on the complex formed between MTX and DNA presented that this complex was indeed fully capable of participating in the formation of a stable intercalation site. Furthermore, the molecular geometries of MTX and the DNA bases (adenine, guanine, cytosine and thymine) were optimized with the aid of the B3LYP/6-31G* method. The properties of the isolated intercalator and its stacking interactions with the adenine...thymine (AT) and guanine...cytosine (GC) nucleic acid base pairs were studied with the DFTB method (density functional tight-binding), an approximate version of the DFT method, that was extended to cover the London dispersion energy. The B3LYP/6-31G* stabilization energies of the intercalator...base pair complexes were found 10.06 kcal/mol and 21.64 kcal/mol for AT...MTX and GC...MTX, respectively. It was concluded that the dispersion energy and the electrostatic interaction contributed to the stability of the intercalator.DNA base pair complexes. The results concluded from the comparison of the DFTB method and the Hartree-fock method point out that these methods show close results and support each other.     

国内靶向制剂的研究现状

目的：研究靶向制剂在中国的发展现状。方法：通过大量国内文献检索，从靶向制剂（主动靶向，被动靶向，物理化学靶向）三方面进行探讨。结果与结论：发现国内靶向制剂潜力巨大，具有较广阔的开发及应用前景。     

新型紫杉烷类抗肿瘤药物卡巴他赛的合成研究

目的改进抗肿瘤药物卡巴他赛的合成方法。方法以10-去乙酰基巴卡亭Ⅲ(10-DABⅢ)为起始原料,经过双甲醚化、酯化偶联、脱保护3步反应制得目标产物。结果与结论采用不同保护基的C-13侧链对酯化偶联反应具有重要的影响;确定了一条实用的制备卡巴他赛的合成路线,3步反应总收率达到41.7%(以10-DABⅢ计)。目标产物的结构经1H-NMR和MS谱确证。该合成路线适于批量合成。     

抗肿瘤药物卡培他滨的合成工艺改进

目的改进抗肿瘤药物卡培他滨的合成工艺.方法经酰化保护的D-核糖与硅醚化的5-氟胞嘧啶反应,生成中间产物2′,3′,5′-O-三苯甲酰-5-氟胞苷(4),后者经皂化、形成酮缩、碘化、氢解及水解等反应合成了5-氟脱氧胞苷,最后与正戊基氯甲酸酯反应生成卡培他滨.结果以D-核糖为起始原料经8步反应合成卡培他滨.结论改进后的合成方法工艺简便、条件温和、原料易得,总收率由文献方法的12%提高为22%,适于工业制备.     

抗癌药西曲瑞克应用研究新进展

抗癌药西曲瑞克是一种新合成的促性腺激素释放激素拮抗剂，通过与内源性LHRH竞争垂体细胞上的膜受体，从而控制黄体生成素（LH）和卵泡刺激素（FSH）的分泌。大量研究表明，西曲瑞克对卵巢癌、前列腺癌、子宫纤维瘤、子宫内膜异位等疾病有较好的疗效，而且对良性前列腺肥大和卵巢过度刺激综合征有预防和改善作用。本文就其应用研究的最新进展进行综述。