一个新药的靶向思考

4月，欧盟批准了沙利度胺（thalidomide）用于多发性骨髓瘤的初始治疗。沙利度胺是上世纪50年代海豹婴儿出生惨剧的始作俑者。科学家后来发现，除了镇静作用外，沙利度胺有抗血管生成和免疫调节作用，包括1998年发现的抑制α肿瘤坏死因子的作用，Celgene公司从这些新的靶标着手进行再开发，最终获得FDA批准作为市场上治疗麻风病的药物，沙利度胺也成为了Celgene公司的旗舰产品。     

沙利度胺抗肿瘤机制及其作用靶点CRBN的研究进展

沙利度胺及其衍生物(来那度胺、泊马度胺)为小分子谷氨酸衍生物,具有很强的免疫调节作用,此外,它们还具有其它重要的生物学作用,如抑制血管新生、致畸,更重要的是,它们具有明显的抗肿瘤活性,能够抑制肿瘤细胞增殖,促进细胞凋亡,特别是针对多发性骨髓瘤(multiple myeloma,MM)的临床治疗中已经发挥重要作用。近年来通过对沙利度胺分子靶标的筛选和其靶分子cereblon(CRBN)发现,为其药理机制的研究提供了新的思路,并为开发新一代无毒副作用和具有更高效抗肿瘤活性的新一代沙利度胺衍生物提供了新的线索。该文将从沙利度胺及其衍生物的作用机制、最新靶点及对MM的治疗作一简单综述。     

沙利度胺的药理作用与研究进展

20世纪50年代沙利度胺曾作为镇静药、镇痛药广泛用于临床，因其严重的致畸作用而禁用。近年来，其药理作用和临床应用研究有了新的进展，通过查阅文献，综述沙利度胺在免疫调节、抑制炎症、抗血管新生等的药理及临床治疗麻风性结节红斑、重症肝炎、肿瘤、风湿病等的研究，结果显示，沙利度胺是一个很有临床应用价值的药物。     

来那度胺在血液和淋巴系统疾病治疗中的应用

目的来那度胺为沙利度胺的衍生物,是新一代的免疫调节剂。它对多种血液和淋巴系统疾病有效,且不良反应较少。本文阐述了来那度胺的药物作用机制,评价了其对多发性骨髓瘤、骨髓增生异常综合征、淋巴瘤、慢性淋巴细胞性白血病、伴骨髓化生的全身性骨髓纤维化疾病和其他恶性血液疾病的疗效,具体介绍了药物不良反应及注意事项。     

来那度胺治疗骨髓增生异常综合征的研究进展

来那度胺（Lenalidomide,CC-5013,商品名Revlimid）是美周Celgene公司开发生产的第2代免疫调节药物,为沙利度胺（thalidomide,反应停）的4-氨基-戊二酞基衍生物,这一化学结构改变使其化学性质比沙利度胺更稳定且具有更强的抑制血管生成和免疫渊节作用,而且神经毒性和致畸性减少。     

沙利度胺的作用机制及抗类风湿性关节炎作用研究进展

沙利度胺于20世纪50年代作为镇静药进入市场，后因其致畸作用于20世纪60年代初退出市场。近年来该药的新作用被开发。随着抑制血管新生、免疫调节和抗炎等方面作用的研究逐步深入，沙利度胺作为免疫抑制药和抑制血管新生药物被广泛应用于临床。类风湿关节炎（RA）是由自身免疫功能紊乱导致的免疫性疾病，主要病理特点与血管新生和免疫失调有关，其中血管新生为该病公认的发病中心环节；传统治疗药物为糖皮质激素、细胞毒药物及免疫抑制剂等，沙利度胺对治疗RA具有潜在临床意义。     

沙利度胺的新用途

现在在美国沙利度胺（thalibomide）只是作为一种研究中的药物在使用。此药1957年作为镇静剂在欧洲上市，4年后由于有严重的致畸作用而撤出市场。此后，发现此药对多种病症有效。沙利度胺的作用机制尚不清楚。它有多种抗炎和免疫调节作用，包括抑制a一肿瘤坏死因子的合成。此药还可抑制血管生成，这可能就是对胎儿四肢致畸作用的原因。亚临床试验（1）麻风结节性红斑（ENL，Ⅱ型麻风反应）：沙利度胺用于严重的或复发性的ENL是非常肯定的，可作为首选药物。反应综合征的特征是有病性皮肤小结、发热、身体不适、消瘦、血管炎和末梢神经炎…     

沙利度胺及其类似物抗肿瘤作用研究进展

沙利度胺（Thalidomide），化学名称α-酞胺哌啶酮。1956年，沙利度胺作为非处方镇静药在欧洲上市，20世纪60年代初因其强烈致畸作用而退出市场，随后的研究发现沙利度胺具有免疫调节作用、抗血管生成作用和T细胞调节作用。1998年，美国食品与药品管理局（FDA）批准沙利度胺用于治疗麻风病结节性红斑（ENL）。近年来研究表明，沙利度胺及其类似物具有抗肿瘤作用，部分类似物的活性高于沙利度胺本身。目前已有大量关于沙利度胺及其类似物的抗肿瘤作用研究报道．     

沙利度胺:一种抗血管生成的抗癌药

虽然沙利度胺的作用机制仍未完全阐明，但有关其所具有的抗血管生成和免疫调节作用已经明确。临床研究证实，沙利度胺治疗浆细胞肿瘤(包括难治性多发性骨髓瘤和原发性巨球蛋白血症)有效，而对其他肿瘤的疗效也在进一步评价中。目前认为，沙利度胺有望在肾癌、前列腺癌、恶性胶质瘤以及卡波济肉瘤的治疗中获得较好的疗效。沙利度胺不良反应一般轻微至中度。且可以处理。使用较大剂量，不良反应发生率可增加。抗血管生成疗法作为耐药病变靶点引人关注。进一步的研究重点在于沙利度胺的抗瘤谱、理想的剂量方案以及最佳联合治疗方案。     

沙利度胺治疗消化道疾病的研究进展

随着科学的进步,消化道疾病的治疗研究不断发展。近年来,病例报道和临床试验都证明沙利度胺正在作为一种有效、可供选择的药物用以治疗消化道疾病。除了可以部分下调促炎症介质肿瘤坏死因子α(TNF-α),抑制由血管内皮生长因子(VEGF)和碱性纤维母细胞生长因子(bFGF)诱导的血管增生,沙利度胺还具有其他免疫调节特性。本文就沙利度胺治疗消化道疾病进行综述。     

沙利度胺衍生物的设计合成及其抗肿瘤活性研究

目的设计合成1，3-二氢-1，3-二氧代．2H-异吲哚-N-取代沙利度胺衍生物。并对其进行体外抗肿瘤活性测试。方法以2．氨基-β-D-吡喃葡萄糖盐酸盐为原料，经过6步反应得到化合物N-（3’，4’，6＇-三乙酰-1’-溴代吡喃葡萄糖）-1,3-二氢-1，3-二氧代-2H-异吲哚，该化合物经过溴代、取代反应得到目标化合物。通过对4T1细胞存活率的测试测定20个目标化合物体外抗肿瘤活性。结果设计合成的20个目标化合物均未见文献报道。所有化合物均经过1H-NMR谱确证，部分化合物经IR、MS谱确证。结论所有目标化合物对4T1细胞均具有-定的抑制生长作用。表明所合成的沙利度胺衍生物均有-定的抗肿瘤活性。     

Immunomodulatory properties of thalidomide analogs: pomalidomide and lenalidomide, experimental and therapeutic applications

Thalidomide has a broad spectrum of anti-cancer activity. Antitumor activity of thalidomide may be related to a number of known properties, including anti-tumor necrosis factor (TNF)-α and T-cell costimulatory and antiangiogenic activities. The therapeutic potential of thalidomide provided motivation to develop more effective derivatives with considerably reduced toxicity. Thalidomide's immunomodulatory (IMiDs) analogs (lenalidomide, CC-5013; CC-4047, ACTIMID) represent a novel class of compounds with numerous effects on the immune system. Some of these analogs are thought to mediate the anticancer and anti-inflammatory effects observed in humans. Thalidomide is currently approved for the treatment of dermal reaction to leprosy and is currently in phase III trials for multiple myeloma (MM). IMiDs inhibit the cytokine's tumor necrosis factor-α (TNF-α), interleukins (IL) 1β, 6, 12, and granulocyte macrophage-colony stimulating factor (GM-CSF). The repression of the tumor necrosis factor-a (TNF-α) expression is the crucial factor of many of the anti-inflammatory properties of thalidomide. The mechanisms underlying many of the anti-inflammatory properties of thalidomide, including its ability to co-stimulate T cells, still remain unclear. Some recent patent are also summarized in this review.     

肽醛类前药衍生物作为蛋白酶体抑制剂的研究(英文)

为了提高经典的肽醛类蛋白酶体抑制剂的稳定性和生物利用度,我们设计合成了4个肽缩醛和2个肽杂缩醛衍生物,并对其进行了酶水平和体外抗肿瘤实验。结果显示,4个肽缩醛化合物几乎没有显示任何活性,表明此类化合物有用作前药的潜质。而2个肽杂缩醛化合物在酶水平和细胞水平均表现出明显的活性,则表明此类化合物可能不是通过前药的形式而发挥作用,进一步优化杂环的结构,有可能发现更好的蛋白酶体抑制剂。     

Genistein and its synthetic analogs as anticancer agents

Genistein, one of the predominant isoflavones derived from soybeans, has been shown beneficial effects in cancer prevention and treatment. There is an accumulating body of experimental evidences suggesting that genistein affects cancer progression by increasing apoptosis, inducing cell cycle arrest,modulating intracellular signaling pathways, and inhibiting invasion and metastasis of cancer cells. During last decade, many researchers have conducted extensive studies by synthesizing amounts of structurally-modified derivatives based on the isoflavone skeleton of genistein to enhance its anticancer activity, some analogs of which possess more potent activities of the prevention and/or treatment of various cancers. In this review, we summarized the current knowledge regarding anticancer effects,structure-activity relationships and action mechanisms of genistein and its synthesized analogs, which would be beneficial to the rational design of new genistein derivatives as anticancer drugs.     

Search for new anti-angiogenic agents with structural analogy with thalidomide

Despite its teratogenic effects, thalidomide has been reintroduced in human anticancer treatment for its anti-angiogenic activity, especially observed in patients with multiple myeloma. Here, we report the synthesis of new analogues designed to increase the thalidomide anti-tumour properties. The anti-angiogenic activity of the compounds was tested on EA.hy 926 endothelial cell lines. In this model, that is easier to manipulate than HUVEC cells, thalidomide is active in a similar dose range as reported on HUVEC cells and one of our compounds is more efficient.     

10-羟基喜树碱衍生物的合成及体外抑制肿瘤活性

目的寻找高效低毒的喜树碱类抗肿瘤新药。方法合成7个喜树碱衍生物（3~9），经¹HNMR，IR，MS分析确证了所合成化合物的结构，经MTT法筛选了对宫颈癌Hela、肝癌BEL-7402、胃癌7901和大肠癌CCL-187瘤株的体外抑制肿瘤活性。结果7个化合物分别对前三种瘤株有效，其中化合物4对前三种瘤株均有较好的体外抑制肿瘤细胞活性，尤其对宫颈癌Hela细胞的抑制活性大于10-羟基喜树碱。结论该类化合物的抗癌活性值得进一步研究。     

The mechanisms of anticancer agents by genistein and synthetic derivatives of isoflavone

Genistein is the most abundant isoflavone in soybeans. It has exhibited diverse biological activities, among these, its anticancer effects is most noteworthy. Through regulating critical cell cycle genes, genistein can inhibit cancer cell growth in vivo and in vitro. It has been reported that genistein can inhibit activation of NF-κB and Akt signaling pathways to induce cell apopt1osis, both pathways are well known for their function to maintain a balance between cell survival and apoptosis. In order to find out more outstanding anticancer isoflavone agents, against cancers extended synthesis of genistein derivatives has been carried out. Some of these synthetic compounds demonstrated higher anticancer activity with lower doses. Based on these results, genistein and its synthetic derivatives may be an emerging new type of anticancer agents.     

Synthesis of some novel 2-substituted benzoxazoles as anticancer, antifungal, and antimicrobial agents

Benzoxazole derivatives show various types of biological properties such as antiviral, antineoplastic, anti-HIV-1, antitubercular, anthelmintic, antimicrobial, and antifungal activities. In the last few years 2-substituted benzoxazole derivatives have been studied extensively for their antitumor, antiviral, and antimicrobial activities. In an effort to identify new candidates that may be of value in designing new, potent, selective, and less toxic anticancer, antiviral, and/or antimicrobial agents, we synthesized 2-[(arylhydrazono) cyanomethyl]-5-chloro benzoxazoles (II), 2-[(arylidene)cyanomethyl]-5-halo benzoxazoles (III), and 2-[(cycloalkylidine)cyanomethyl]-5-chlorobenzoxazoles (IV), and tested them for anticancer, antifungal, and antibacterial activities. Some of these (compounds 11, 14) were found to possess anticancer activity and remarkable antifungal as well as antibacterial activities.     

Shikonin and its derivatives: a patent review

Introduction: Shikonin and its derivatives are the main components of red pigment extracts from Lithospermum erythrorhizon, whose medicinal properties have been confirmed for a long history, and have aroused great interest as the hallmark molecules responsible for their significant biological activities, especially for their striking anticancer effects. Areas covered: Areas covered in this paper include a review of the total synthesis, biological effects and mechanisms of shikonin and its derivatives for their anticancer activities in the past decade, basing on literature and patents. The current state and problems are also discussed. Expert opinion: At present, screening for anticancer shikonin derivatives is based on cellular level to find compounds with stronger cytotoxicity. Though several compounds have been discovered with striking cytotoxicity in vitro, however, no selectivity was observed and undoubtedly, the further outcomes have been disappointing because of their great damage to normal cells. Meanwhile, the presumed mechanisms of action are also established in terms of their cytotoxicity. From a pharmacological point of view, most of the shikonin derivatives are at an early stage of their development, and thus it is difficult to determine the exact effectiveness in cancer treatment. With research in this field going deeper, it can be expected that, despite the difficulties, shikonin derivatives as potential anticancer agents will soon follow.     

Betulinic acid derivatives as anticancer agents: structure activity relationship

Betulinic acid, a pentacyclic triterpene, is widely distributed throughout the tropics. It possesses several biological properties such as anticancer, anti-inflammatory, antiviral, antiseptic, antimalarial, spermicidal, antimicrobial, antileshmanial, antihelmentic and antifeedent activities. However, betulinic acid was highly regarded for its anticancer and anti-HIV activities. Anticancer role of betulinic acid appeared by inducing apoptosis in cells irrespective of their p53 status. Due to high order safety in betulinic acid, a number of structural modifications carried out to improve its potency and efficacy. The C-1, C-2, C-3, C-4, C-20 and C-28 positions are the diversity centers in betulinic acid, and the derivatives resulted on various structural modifications at these positions screened for their anticancer activity. This review presents the structure activity relationship carried out on C-1, C-2, C-3, C-4, C-20, C-28, A-ring, D-ring and E-ring modified betulinic acid derivatives. We have compiled the most active betulinic acid derivatives along with their activity profile in each series. Structure activity relationship studies revealed that C-28 carboxylic acid was essential for the cytotoxicity. The halo substituent at C-2 position in betulinic acid enhanced the cytotoxicity. Though the relation of the cytotoxicity with the nature of substituents at C-3 position could not be generalized but the ester functionality appeared to be a better substituent for enhancing the cytotoxicity. An interesting observation is that the three rings skeleton (A, B and C rings) had played an important role in eliciting anticancer activity, which could be a new molecular skeleton to design new anticancer drugs.