多靶点叶酸拮抗剂培美曲塞

叶酸拮抗剂培美曲塞(力比泰,pemetrexed,Alimta)作用于与叶酸代谢相关的多个靶点,近年来在肿瘤治疗方面的应用逐渐增多,本文介绍其作用机制以及临床疗效与安全性,并对其耐药性产生机制、不良反应特点及其最新研究进展进行了综述.     

抗肿瘤药来曲唑的合成工艺改进

目的研究来曲唑的合成新工艺。方法以对甲基苯甲腈和对氯苯甲腈为原料,经缩合、溴化、N-烃化、重氮化脱氨基制得来曲唑。结果与结论目标产物的结构通过1H-NMR和ESI-MS谱确证,摩尔总收率为44.6%。改进后的制备工艺具有原料价廉易得、反应条件温和、收率高、选择性好等优点,适合来曲唑的工业化生产。     

培美曲塞二钠的合成

对碘苯甲酸甲酯与烯丙醇缩合,与硝基甲烷反应得1-硝基-4-(甲氧基羰基苯基)-1-丁烯,继而与2,6-二氨基-4(3H)-嘧啶酮加成,再经Nef反应脱硝基、闭环、水解得4-[2-(2-氨基-4-氧代-4,7-二氢-3H-吡咯并[2,3-d]嘧啶-5-基)乙基]苯甲酸,最后与L-谷氨酸二乙酯缩合、水解、中和得培美曲塞二钠,总收率1.8%.     

培美曲塞的临床应用进展

培美曲塞临床应用广泛,对多种恶性肿瘤有效。本文综述多靶点抗肿瘤药培美曲塞在临床恶性胸膜间皮瘤,非小细胞肺癌以及胃癌等消化系统肿瘤中的应用进展。     

培美曲塞二钠的合成

对碘苯甲酸甲酯与3-丁烯醇反应后溴代得4-（3-溴-4-氧代丁基）苯甲酸甲酯，与2，4-二氨基-6-羟基嘧啶反应后，再经水解得重要中间体2-氨基-4-氧代-5-[2-（4-羧基苯基）乙基]-4，7-二氢-3H-吡咯并[2，3-d]嘧啶，最后与L-谷氨酸二乙酯盐酸盐酰化、水解得培美曲塞二钠，总收率16％。     

培美曲塞二钠的合成路线

培美曲塞二钠是唯一治疗恶性胸膜间皮瘤(MPM)的药物。本文根据不同的原料和中间体,通过图表形式归纳了培美曲塞二钠的合成路线。     

抗肿瘤新药——培美曲塞

培美曲塞是一种作用于叶酸代谢过程中 多种靶点的抗肿瘤新药。临床前研究及临床研究证 实该药对多种实体肿瘤有明确的抗瘤活性,包括肺 癌、乳腺癌、胰腺癌、卵巢癌等,特别是对恶性胸膜间 皮瘤的治疗。药物的不良反应主要包括骨髓抑制和 皮疹,在补充叶酸和维生素B12的情况下,不良反应 明显减轻,病人耐受性良好。本文就近年来该药的 研究进展作一简要的介绍。     

来曲唑的合成

4-溴甲基苄腈与1,2,4-1H-三唑钠反应得4-[(1H-1,2,4-三唑-1-基)甲基]苄腈,然后在叔丁醇钾的作用下与4-氟苄腈反应得来曲唑,总收率为54.8%。     

Pemetrexed disodium in ovarian cancer treatment

Introduction: Current therapies for recurrent ovarian cancer (OC) yield relatively modest improvements in survival. Many drugs are available but recently a renewed interest is addressed on antimetabolite drugs. Pemetrexed (PEM) is a multitargeted antifolate cytotoxic agent mainly used in lung cancer.

Areas covered: This review summarizes the available evidence on the use of PEM in the treatment of OC. This article consists of material obtained via Medline, PubMed and EMBASE literature searches, up to November 2011. Currently available published data on mechanism of action, pharmacokinetics, safety and efficacy of PEM in the treatment of recurrent OC are described.

Expert opinion: Eight trials evaluated the use of PEM in OC patients. Studies using PEM in combination with carboplatin in platinum-sensitive OC suggested that the response rate is similar to other combination therapies. However, based on the absence of randomized trials comparing this doublet with currently used combination treatments, it is difficult to draw conclusions on the efficacy of PEM regimens in these patients. In platinum-resistant OC patients, two studies suggested that PEM alone might have equivalent activity to other single-agent treatment. Further pharmacogenomic and clinical data are warranted to better define the role of PEM in the treatment of recurrent OC.     

Pazopanib,a potent orally administered small-molecule multitargeted tyrosine kinase inhibitor for renal cell carcinoma

Background: The recent approvals of sunitinib, sorafenib and temsirolimus have revolutionized the management of renal cell carcinoma (RCC). Pazopanib (GW-786034) is a second-generation multitargeted tyrosine kinase inhibitor against VEGFR-1, 2 and 3, platelet-derived growth factor receptor (PDGFR)-α, PDGFR-β and c-kit. Objective: Data supporting the development of pazopanib for RCC are reviewed. Methods: Preclinical and clinical data available for pazopanib are presented. Results: Preclinical evaluation has revealed excellent anti-angiogenic and anti-tumor activity in several mouse models. A Phase II clinical trial of pazopanib in untreated or cytokine/bevacizumab pretreated RCC has demonstrated promising activity accompanied by a favorable toxicity profile. A placebo-controlled Phase III trial is ongoing in untreated or cytokine-treated patients with RCC. Ongoing trials are further evaluating pazopanib in a variety of other malignancies.     

Investigational multitargeted kinase inhibitors in development for head and neck neoplasms

Introduction: Despite advances in treatment, head and neck squamous cell carcinoma (HNSCC) survival rates remain stagnant. Current treatment is associated with significant toxicities and includes chemotherapy, radiation, surgery, and few targeted treatments. Targeted treatments, epidermal growth factor receptor (EGFR)-targeted agent, cetuximab, and immune checkpoint inhibitors, pembrolizumab and nivolumab, show improved toxicity profiles and modestly improved survival in select patients. An urgent need remains to identify novel targeted treatments for single-agent or combined therapy use.

Areas covered: Multitargeted kinase inhibitors are small molecule inhibitors with limited toxicity. This review will focus on early-stage investigations of multitargeted tyrosine kinase inhibitors (m-TKIs) (those that target at least two tyrosine kinases) for HNSCC. Preclinical and early trials investigating m-TKIs for various disease settings of HNSCC will be evaluated for efficacy, identification of significant biomarkers and potential for combination therapy.

Expert opinion: Few single agent m-TKIs have demonstrated efficacy in unselected HNSCC populations. The most promising clinical results have been obtained when m-TKIs are tested in combination with other therapies, including immunotherapy, or in mutation-defined subgroups of patients. The future success of m-TKIs will rely on identification, in preclinical models and clinical trials, of predictive biomarkers of response and mechanisms of innate and acquired resistance.     

A phase II trial of pemetrexed in patients with metastatic renal cancer

Background. Metastatic renal cell carcinoma (RCC) is rising in incidence but remains difficult to treat. This clinical trial evaluated the effects of pemetrexed (multitargeted antifolate, ALIMTA®) for the treatment of metastatic RCC. Patients and methods. Patients were required to have histological diagnosis of metastatic RCC with measurable disease and no prior chemotherapy. In addition, patients were required to have a World Health Organization (WHO) performance status of 0–2 and adequate bone marrow reserve. Patients received pemetrexed at a dose of 600mg/m² as a 10min infusion every 3 weeks. Patients did not receive folic acid or vitamin B₁₂ supplementation. Results. Thirty-nine patients were enrolled and thirty two were evaluable for response. Three patients had a partial response for a response rate of 9% (95% CI 2–25%). The median time to progressive disease was 10.5 months. Of the nonresponders, twenty two had stable disease (median duration was 5.8 months; range 1.5–27.7) and seven had progressive disease (median time to progression was 5.4 months). Median time to progression for all qualified patients was 5.7 months. Common toxicities experienced were diarrhea and infection. Fatigue, stomatitis, and rash were also reported. The most common hematologic toxicity was grade 3/4 lymphopenia in 76% of patients. Leukopenia, granulocytopenia, and thrombocytopenia were also frequently reported. Conclusion. Single-agent pemetrexed has moderate activity in the treatment of metastatic RCC and should be investigated in combination with other potential active agents, as first-line treatment.     

Antimetabolites and cancer: emerging data with a focus on antifolates

Antimetabolites, especially antifolates, play an important role in the treatment of a variety of both malignant, and non-malignant diseases, such as rheumatoid arthritis, and bacterial and parasitic infections. Recently, new antimetabolites have become an area for anticancer drug expansion. Gemcitabine has emerged as an important new agent in several tumour types, including non-small cell lung cancer, pancreatic, bladder, breast and ovarian cancers. Capecitabine is an intriguing new prodrug, offering tumour selectivity and prolonged tumour exposure to 5-FU. More potent thymidylate synthase inhibitors have also been developed; raltitrexed and pemetrexed are now commercially available for the treatment of mesothelioma, non-small cell lung cancer and other solid cancer types. This review will describe the most recent findings and their potential clinical applications.     

抗抑郁新药马来酸氟伏沙明的合成

目的研究抗抑郁新药马来酸氟伏沙明的合成.方法以苯甲酸乙酯为起始原料,经取代、氨解、水解、成盐4步反应合成马来酸氟伏沙明(8).结果与结论以苯甲酸乙酯为起始原料,合成了马来酸氟伏沙明,总收率为51%.改进了中间体2-溴乙基邻苯二甲酰亚胺(4)的合成工艺.     

培美曲塞的合成

目的研究培美曲塞的合成方法。方法以对碘苯甲酸为起始原料,经氯化、酯化、缩合、环合、水解、成盐等十步反应合成培美曲塞。结果合成的目标化合物,其结构经核磁共振氢谱、核磁共振碳谱、质谱及元素分析确证。结论改进后的合成路线与文献报道的合成路线相比,反应步骤简化,收率进一步提高。     

利培酮的合成

目的研究利培酮的合成工艺。方法以4-哌啶甲酸为原料，经氨基保护及氯代得到1-乙氧甲酰基-4-哌啶甲酰氯（3）-3与1．3-二氟苯经傅-克酰基化、脱氨基保护、肟化、环合、成盐得到6-氟-3-（4-哌啶基）-1,2-苯并异唔唑盐酸盐（7）。7和3-（2-氯乙基）-6，7，8,9-四氢-2-甲基-4H-吡啶并[1，2-a]嘧啶-4-酮在碱催化下缩合得到利培酮（1）。结果与结论合成的利培酮经^1H-NMR、^13C-NMR、MS确证结构．总收率21．5%。该合成工艺原料价廉易得、操作简便，适合工业化生产。