*研究快报* 通过Bergman环化聚合反应合成侧链含有苯丙氨酸的手性聚合物

以直径为140 mm水力旋流器作为研究对象,采用计算流体力学（CFD）技术对旋流器内部流场进行数值模拟,并对所建立的模型进行激光粒子图像测速（PIV）实验验证。基于数值模拟和实验结果,分析了旋流器内部压力、切向速度、轴向速度和径向速度的分布。利用PIV技术对旋流器内部流场进行测量,考察了不同入口速度下旋流器圆柱段区域瞬态速度场。通过对比数值计算与测试结果表明：CFD模拟可以有效预测水力旋流器内部流场分布,帮助探索旋流器内的流动状态和分离机理;利用PIV技术测量旋流器内部流动特性和速度分布,其测量结果与CFD计算结果吻合良好,验证了数值模型的准确性。     

抗癌抗生素C1027与单克隆抗体偶联物的抗肿瘤作用

抗癌抗生素C1027对癌细胞有强烈杀伤作用,比阿霉素强10000倍以上,C1027与癌细胞接触10min即显示对DNA合成的强烈抑制作用,C1027分子由发色团与蛋白质两部分构成;发色团是烯二炔新化合物,是C1027分子的主要活性部分.C1027分子可拆分与重建,重建的C1027同样有高度抗肿瘤活性.通过新的交联方法可制备C1027与单抗的强化偶联物.体外、体内试验表明.C1027单抗偶联物对肿瘤靶细胞有很强的特异性杀伤作用;对移植于探鼠的人体肝癌、胃癌有显著疗效,在可耐受剂量,肿瘤抑制率达85%(P<0.01).研究结果显示,C1027作为高效“弹头”药物,可用于研制新的小型化高效抗肿瘤导向药物.     

双烯二炔类抗癌药——新制癌菌素的研究进展

双烯二炔类抗生素具有很高的抗癌活性,可裂解 DNA 链,具有很强的细胞毒性,用于癌症的临床治疗。新制癌菌素是其家族中的一员,由制癌链霉菌（Streptomyces carzinostaticus）产生,它是第一个也是最广泛应用的烯二炔类抗生素之一。综述新制癌菌素的作用机制及其穿膜机制的文献资料,并对其应用前景作一分析与展望。     

烯二炔类抗肿瘤抗生素全合成研究.含芳环烯二炔单元开链衍生物的合成

以 2 -溴苯甲醛为原料 ,经 6步反应 ,得到含芳环十元环状烯二炔单元开链衍生物。共合成 12个新化合物 ,其结构均经1 NHMR谱和质谱确证     

烯二炔类高效抗肿瘤抗生素Calicheamicin的研究进展

烯二炔类抗生素是由放线菌产生的一类高活性抗肿瘤化合物,因其具有烯二炔环这一独特结构以及很强的抗肿瘤活性而备受人们的关注.其中,针对抗生素calicheamicin(CLM)的研究较为全面,并已用于临床治疗.本文对CLM的发现、结构特点与作用机制、单克隆抗体-CLM偶联物的临床疗效及毒副作用、CLM的化学修饰与合成作简要综述.     

一株新的小单孢菌C-3509抗肿瘤活性成分的分离、纯化和结构鉴定

目的:分离纯化小单孢菌C-3509中的抗肿瘤活性成分,并阐明其结构特征。方法:采用多种层析法进行C-3509抗肿瘤活性成分的分离纯化;通过紫外扫描、高分辨电喷雾质谱和核磁共振氢谱揭示其结构特征;利用DNA断裂法检测其抗肿瘤活性。结果:通过对C-3609菌株发酵和活性检测,分离、纯化得到了抗肿瘤活性成分C-3509B;进一步对C-3509B组分进行初步光谱分析与结构鉴定,结果显示该组分结构特征与抗肿瘤抗生素calicheamicinγ1I一致。结论:C-3509B可能是十元环烯二炔calicheamicins的γ1I组分。     

Hsp90 Inhibitor Geldanamycin Enhances the Antitumor Efficacy of Enediyne Lidamycin in Association with Reduced DNA Damage Repair

Inhibition of heat shock protein 90 (Hsp90) leads to inappropriate processing of proteins involved in DNA damage repair pathways after DNA damage and may enhance tumor cell radio- and chemo-therapy sensitivity. To investigate the potentiation of antitumor efficacy of lidamycin (LDM), an enediyne agent by the Hsp90 inhibitorgeldanamycin (GDM), and possible mechanisms, we have determined effects on ovarian cancer SKOV-3, hepatoma Bel-7402 and HepG2 cells by MTT assay, apoptosis assay, and cell cycle analysis. DNA damagewas investigated with H2AX C-terminal phosphorylation (γH2AX) assays. We found that GDM synergistically sensitized SKOV-3 and Bel-7402 cells to the enediyne LDM, and this was accompanied by increased apoptosis. GDM pretreatment resulted in a greater LDM-induced DNA damage and reduced DNA repair as compared with LDM alone. However, in HepG2 cells GDM did not show significant sensitizing effects both in MTT assay and in DNA damage repair. Abrogation of LDM-induced G2/M arrest by GDM was found in SKOV-3 but not inHepG2 cells. Furthermore, the expression of ATM, related to DNA damage repair responses, was also decreased by GDM in SKOV-3 and Bel-7402 cells but not in HepG2 cells. These results demonstrate that Hsp90 inhibitors may potentiate the antitumor efficacy of LDM, possibly by reducing the repair of LDM-induced DNA damage.     

Uncialamycin-based antibody–drug conjugates: Unique enediyne ADCs exhibiting bystander killing effect

Antibody–drug conjugates (ADCs) have emerged as valuable targeted anticancer therapeutics with at least 11 approved therapies and over 80 advancing through clinical trials. Enediyne DNA-damaging payloads represented by the flagship of this family of antitumor agents, N-acetyl calicheamicin γ1I, have a proven success track record. However, they pose a significant synthetic challenge in the development and optimization of linker drugs. We have recently reported a streamlined total synthesis of uncialamycin, another representative of the enediyne class of compounds, with compelling synthetic accessibility. Here we report the synthesis and evaluation of uncialamycin ADCs featuring a variety of cleavable and noncleavable linkers. We have discovered that uncialamycin ADCs display a strong bystander killing effect and are highly selective and cytotoxic in vitro and in vivo.

Although the essential concept of antibody–drug conjugates (ADCs) was proposed by Paul Ehrlich more than a century ago (1), it was only at the dawn of the 21st century that this concept was translated into a targeted cancer therapy when Mylotarg (2, 3) was approved for clinical use for the treatment of acute myeloid leukemia. Since then a number of other ADCs have been approved as clinical therapies (4), including Adcetris (5), Kadcyla (6), Besponsa (7), Polivy (8), Padcev (9), Enhertu (10), Trodelvy (11), Blenrep (12), Lumoxiti (13), and Zynlonta (14). These successes emerged as a result of multidisciplinary efforts to ensure fine-tuning and optimizing the various components of the ADCs, including the payload, the linker, the linker-drug, the antibody, and the final ADC. The approval of Mylotarg (carrying the N-acetylated version of calicheamicin γ1I [1], N-acetyl calicheamicin γ1I [2], as the payload) by the Food and Drug Administration in 2000 validated our earlier disclosure of an ADC (15) carrying a totally synthetic thioacetate analog (calicheamicin θ1I [3]) (16) of calicheamicin γ1I (1) that exhibited suppression of growth and dissemination of liver metastases in a syngeneic model of murine neuroblastoma. Inspired by these calicheamicin γ1I payloads, and their ADCs, we undertook the total synthesis (17, 18) of uncialamycin (19) (4; Fig. 1), a natural product whose structure resembles that of calicheamicin γ1I with regard to the 10-membered ring enediyne structural motif. Our asymmetric and successful total synthesis of uncialamycin (18) facilitated not only its absolute configuration assignment but also the design, synthesis, and biological evaluation of numerous uncialamycin analogs. From these diverse structures, methylamine analog 5 (Fig. 1) was chosen as a payload for further advancement and investigation by virtue of its high potency and convenient handle for linker attachment. The envisioned sequence was to include linker-drug design and synthesis, attachment onto appropriate antibodies to afford ADCs, and in vitro and in vivo biological evaluation as targeted anticancer agents.Open in a separate windowFig. 1.Molecular structures of natural product calicheamicin γ1I (1), N-acetyl calicheamicin γ1I (2), totally synthetic calicheamicin θ1I (3), natural product uncialamycin (4), and potent uncialamycin analog.     

基于马来酰亚胺的超支化聚烯二炔的合成

通过酰亚胺化和氯碘交换反应合成了3种含有碘和端基炔三官能团的AB₂型单体,并由它们通过Sonogashira交叉偶联聚合反应制备了一系列具有烯二炔重复单元的超支化聚合物（HBEPs）。采用核磁（NMR）、傅里叶红外光谱（FT-IR）、凝胶渗透色谱（GPC）、动态光散射（DLS）、差示量热扫描（DSC）、紫外-可见（UV-Vis）和荧光光谱等测试手段对HBEPs的结构进行了一系列测试和表征,研究了主链中取代基对聚合物的物理和化学性能的影响。结果表明：HBEPs的支化度最高接近于1,其荧光特性与自身结构的共轭程度有关。     

具有烯二炔类抗生素产生能力的稀有放线菌的筛选

高质量的微生物天然产物库是新药研发的重要来源,目前我国已经建立了较大规模的微生物产物库,建立高效准确的筛选模型来筛选烯二炔类抗肿瘤抗生素对已建立的微生物产物库进行筛选对于新药研发至关重要.本文重点讨论了目前已经较为常用的烯二炔类抗生素产生菌的筛选方法,包括基于活性与基因的筛选模型和精原细胞筛选模型,之后根据甄永苏院士的团队所做的内容提出两种新的理论上可行而且未来有可能被构建的筛选模型.