WO2020248327A1 - 一种脂肪合成酶抑制剂及其应用 - Google Patents
一种脂肪合成酶抑制剂及其应用 Download PDFInfo
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- WO2020248327A1 WO2020248327A1 PCT/CN2019/096319 CN2019096319W WO2020248327A1 WO 2020248327 A1 WO2020248327 A1 WO 2020248327A1 CN 2019096319 W CN2019096319 W CN 2019096319W WO 2020248327 A1 WO2020248327 A1 WO 2020248327A1
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- fatty acid
- compound
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Definitions
- the invention belongs to the field of medical biotechnology, and specifically relates to a liposynthetic enzyme inhibitor and its application.
- FASN includes acetyltransferase (AT), malonyltransferase (MT), ⁇ -ketoacyl synthase (KS), ⁇ -ketoacyl reductase (KR), ⁇ -hydroxyacyl dehydratase (HD ), enoyl reductase (ER) and thioesterase (TE) and other 7 functional domains, it can be divided into two subtypes, type I and type II.
- AT acetyltransferase
- MT malonyltransferase
- KS ⁇ -ketoacyl synthase
- KR ⁇ -ketoacyl reductase
- HD ⁇ -hydroxyacyl dehydratase
- ER enoyl reductase
- TE thioesterase
- FASN in bacteria and plants belongs to type II, which is a multi-enzyme system composed of the above 7 functional domains as independent enzymes; FASN in humans and other mammals belongs to type I, which includes the above 7 functions
- a single-chain multifunctional enzyme composed of domains, which is encoded by a single gene and has a relative molecular mass of 250 ku.
- FASN can be expressed in various tissues such as liver and fat. Its function is to synthesize carbohydrates into fatty acids and store them in the form of triglycerides.
- FASN also has some special functions. For example, during lactation, when it co-exists with thioesterase, FASN can act to produce medium-chain fatty acids that are easy for babies to digest.
- FASN is highly expressed in the liver and fat cells of obese patients, and tumor cells of various tumor patients. FASN has become a new drug target for studying such diseases. The study of FASN inhibitors is of great significance for inhibiting the biosynthesis of endogenous fatty acids, thereby effectively controlling the occurrence and development of tumors, obesity and various related metabolic syndromes.
- Y is selected from nitrogen, oxygen or sulfur.
- the second object of the present invention is to apply the compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof in the preparation or development of drugs for the treatment of cancer, fatty acid metabolism diseases or immune diseases.
- the fourth object of the present invention is to provide a preparation or development of a medicine for treating cancer, which contains the compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof.
- the medicine also contains other medically acceptable excipients, including binders, fillers, disintegrants, lubricants, antioxidants, correctives, fragrances, cosolvents, emulsifiers, solubilizers, and osmotic pressure regulators Agent, coloring agent, etc.
- binders including binders, fillers, disintegrants, lubricants, antioxidants, correctives, fragrances, cosolvents, emulsifiers, solubilizers, and osmotic pressure regulators Agent, coloring agent, etc.
- Figure 7 shows the effect of the compound represented by formula I on the accumulation of nematode lipid droplets
- FASN(%) [1-(FASN inhibitor ⁇ FASN control )] ⁇ 100%;
- IC50 halfmaximal inhibitory concentration refers to the half-inhibitory concentration of the measured antagonist. It can indicate that a certain concentration of a certain drug or substance (inhibitor) induces tumor cell apoptosis by 50%. This concentration is called 50% inhibitory concentration, that is, the concentration corresponding to when the ratio of apoptotic cells to the total number of cells is equal to 50% .
- the IC50 value can be used to measure the ability of a drug to induce apoptosis, that is, the stronger the inducing ability, the lower the value, and it can also indicate the degree of tolerance of a certain cell to the drug.
- Western-blot detection used the change of FASN protein expression in colon cancer cells HCT116 treated with compound I-1, and the change of protein expression in colon cancer cells treated with cerulenin as a positive control.
- the specific steps of Western-blot are as follows:
- Figure 5 shows the effect of the compound of formula I on the fatty acid content and composition of prostate cancer cell PC-3 and colon cancer cell HCT116.
- the types of fatty acids include 18:2, 18:1, 18:0, 16:1, 16:0 and 14:0. It can be seen from Figure 5 that the total fatty acid content of PC-3 and HCT116 cells treated with the compound of formula I was significantly lower than that of the control group, and the fatty acid content of 16:0 was also lower than that of the control group, indicating that the compound of formula I could inhibit PC -3 and the synthesis of fatty acids in HCT116, change the distribution of fatty acids in tumor cells, thereby affecting tumor cell metabolism. Inhibition of fatty acid synthesis reduces structural lipids and energy required for cell proliferation. It is an important reason for inhibiting tumor proliferation and causing tumor cell apoptosis. Therefore, compound I-1 can inhibit the occurrence and development of tumors and has important clinical applications. Application prospects.
- the transplanted tumor model was successfully selected in nude mice (tumor formation rate 100%).
- the nude mice were adapted to rearing for 7 days, and the subcutaneous cancer cell transplantation experiment was performed. After the tumor was visible to the naked eye, intraperitoneal injection was performed every 2 days.
- the injection dose was Compound I-1 at 5 mg/kg was used as a control in the solvent injection group, with 5 rats in each group. After 4 weeks of administration, the tumors were taken and weighed (Figure 9A).
- compound I-1 has obvious inhibitory effect on mouse tumors, and compound I-1 has important application prospects as a new type of anti-tumor drug.
- the compound I-1 to compound I-8 provided by the present invention can effectively inhibit fatty acid synthase activity.
- compound I-1 has the highest inhibition rate on fatty acid synthase (FASN), which is 58.63%.
- Fatty acid synthase (FASN) participates in tumor fatty acid metabolism and cell cycle processes, and plays an important role in tumor growth, invasion and migration.
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Abstract
一种脂肪酸合成酶抑制剂及其应用，属于医药生物技术领域。脂肪酸合成酶抑制剂能够显著抑制脂肪酸合成酶的活性，并不影响正常表达，且能够调节细胞中脂肪酸的比例。脂肪酸合成酶抑制剂同时具有肿瘤增殖抑制作用，能够使肿瘤细胞的生长周期停滞在间期，阻止肿瘤细胞分裂，抑制肿瘤细胞增殖，促进肿瘤细胞凋亡，发挥对肿瘤的治疗效果，可用于治疗肿瘤和代谢相关疾病的药物，具有重要的临床应用前景。
Description
本发明属于医药生物技术领域，具体涉及一种脂肪合成酶抑制剂及其应用。
人体内的脂肪酸一方面是直接来源于外界摄入的外源性脂肪酸，另一方面是体内自身合成的内源性脂肪酸。脂肪酸合成酶(fatty acid synthase，FASN)是生物体内源性脂肪酸合成过程的关键酶，它通过催化乙酰辅酶A和丙二酰辅酶A而生成长链脂肪酸。FASN包括乙酰基转移酶(AT)、丙二酰基转移酶(MT)、β-酮脂酰合酶(KS)、β-酮脂酰还原酶(KR)、β-羟脂酰脱水酶(HD)、烯脂酰还原酶(ER)及硫酯酶(TE)等7个功能域，它可分为Ⅰ型和Ⅱ型两种亚型。细菌和植物中的FASN属Ⅱ型，是由以上7个功能域分别作为独立的酶而聚合在一起的多酶体系；人类及其他哺乳类动物的FASN属Ⅰ型，是由包括以上7个功能域组成的一个单链多功能酶，其由单基因编码，相对分子质量为250ku。在正常情况下，FASN可在肝脏和脂肪等各种组织中表达，其功能是将碳水化合物合成脂肪酸，以甘油三酯的形式储存。FASN还有一些特殊的功能，如在哺乳期，当与硫酯酶共同存在时，FASN可作用产生易于婴儿消化的中链脂肪酸。在正常的生理状态下，FASN受饮食和激素的调节。碳水化合物的摄取，甲状腺、胰岛素、糖皮质激素均可上调FASN和脂肪酸合成，不饱和脂肪酸、cAMP、胰高血糖素下调FASN和脂肪酸合成。
近年发现，FASN与肥胖密切相关。FASN在人的肝脏和脂肪组织中有较高的表达，特别是肝脏，其脂肪酸合成能力较脂肪组织高8～9倍，并且表达水平受摄食成分和激素水平的影响，含碳水化合物的饮食通过刺激FASN的高表达诱导脂肪的生成。因此开发FASN抑制剂有望为肥胖症的治疗开辟新途径。FASN特异性的小分子抑制剂可通过抑制FASN而减少脂肪酸的合成；而且，由于脂肪酸合成受阻，导致其底物丙二酰辅酶A浓度升高，可直接作用于下丘脑的进食中枢，抑制促进摄食的神经肽Y的分泌，从而导致进食抑制。同时，在外周组织如肝脏、脂肪组织中，可以提高肉毒碱软脂酰转移酶-1的活性，从而增强脂肪酸的氧化和能量的消耗，通过代偿性消耗体内过多的脂肪而达到减肥的目的。动物实验还显示，FASN抑制剂还可以改善非胰岛素依赖型糖尿病，降低高血压、冠状动脉栓塞及其他肥胖并发症的症状，降低发病率。
自80年代开始，研究者先后在乳腺癌、结直肠癌、前列腺癌、卵巢癌、子宫内膜癌等组织中发现FASN，并且FASN表达远高于正常组织。研究表明，抑制FASN或者减少其表达，可以有效控制肿瘤细胞的增生或诱导其凋亡。目前FASN调节肿瘤的机制尚不明确，有研究者认为，抑制FASN使提供细胞增殖所需的结构脂质和能量减少是造成肿瘤细胞凋亡的原因。也有研究者推测胞内丙二酰辅酶A浓度升高是抑制FASN造成肿瘤细胞凋亡的主要原因。还有研究显示，用FASN抑制剂后，肿瘤细胞停滞在G0期，表明脂肪酸合成与细胞周期相关。抑制FASN能快速、大量抑制肿瘤细胞DNA复制，使S期延迟，表明脂肪酸合成通路及DNA合成的活性与肿瘤细胞的增殖有关。
FASN在肥胖患者的肝脏及脂肪细胞、各种肿瘤患者的肿瘤细胞中都有较高的表达，FASN已成为研究此类疾病的药物新靶标。FASN抑制剂的研究，对于抑制内源性脂肪酸的生物合成，进而有效控制肿瘤、肥胖及各种相关代谢综合症等的发生、发展有着重要的意义。
发明内容
为了解决上述问题，本发明提供了通式(I)所示的化合物或其药学上可接受的盐在制备用于抑制脂肪酸合成酶药物中的应用，如下通式(I)所示的化合物，或其药学上可接受的盐：
其中，
为单键或双键；R
1、R
2分别独立地选自羟基、卤素、C1-C4烷基、C1-C4烷氧基中任意一种；
环A为
U、V、Z分别独立的选自CH、N、NH；R
3、R
4分别独立地选自卤素、羟基、芳氧基和烷氧基中任意一种；虚线表示含有或者不含有，即环A含为取代苯基或者取代苯并杂环基；
Q为至少一个杂原子或不包含杂原子的C
1～5直链或支链烃基，所述杂原子分别独立地选自氮、氧和硫；
L为酮基或亚胺基；
W选自-(CH
2)
a、-(CH
2)
a-C(O)-、-(CH
2)
a-OC(O)-、-(CH
2)
n-C(O)O-中任意一种，其中a为0-3的自然数；
X选自-N(R)
mN(R)
n-、-C(O)N(R)
n-或-N(R)
nC(O)-，m和n分别独立地为0或1；R独立地为氢、卤素或苯基；
Y选自氮、氧或硫。
在本发明的一种实施方式中，所述环A为单环芳基、萘基、[1,8]萘啶基、苯并噁唑基、苯并噻唑基、苯并咪唑基、苯并三唑基、吲哚基、苯并-1,3-二氧杂环戊烯基、苯并二氧杂环己烷基、苯并噻二唑基、吲唑基、苯并呋喃基、喹啉基、异喹啉基、噁唑并[5,4-b]吡啶基或噁唑并[5,4-c]吡啶基。
在本发明的一种实施方式中，所述Q为端基为-N(R)-、-S-、-O-、-SO-、-SO
2-、-NRC(O)-、-C(O)NR-、-N(R)SO
2-、-SO
2N(R)-、-OC(O)-或-C(O)O-的C
1～5直链或支链烃基。
在本发明的一种实施方式中，所述Q中含有至少一个双键。
在本发明的一种实施方式中，所述通式(I)所示化合物药学上可接受的盐包括：乳酸盐、盐酸盐、磷酸盐、醋酸盐、苹果酸盐、枸椽酸盐或天冬氨酸盐。
在本发明的一种实施方式中，所述通式(I)化合物选自下述结构：
本发明提供的通式(I)所示的化合物或其药学上可接受的盐，可作为脂肪酸合成酶抑制剂，用于抑制脂肪酸合成酶的活性，在调节脂肪酸组成中的发挥作用。
本发明的第二个目的是将上述通式(I)所示的化合物或其药学上可接受的盐应用于制备或开发治疗癌症、脂肪酸代谢疾病或免疫性疾病的药物中。
本发明的第三个目的是提供一种制备或开发用于治疗脂肪酸代谢疾病的药物，所述药物中包含上述通式(I)所示的化合物或其药学上可接受的盐。
所述脂肪酸代谢疾病选自肥胖症、心脑血管疾病、高脂血症、原发性肥胖、肺动脉高血压、Hodgkin疾病、肠易激综合征、脑血管意外、动脉粥样硬化和糖尿病、血管球性肾炎、病毒感染。
本发明的第四个目的是提供一种制备或开发用于治疗癌症的药物，所述药物中包含上述通式(I)所示的化合物或其药学上可接受的盐。
所述癌症选自卵巢癌、乳腺癌、子宫癌、结肠癌、子宫颈癌、肺癌、前列腺癌、睾丸癌、胸腺癌、皮肤癌、膀胱癌、胰腺癌、白血病、淋巴瘤、非小细胞肺癌、小细胞肺癌、多发性骨瘤癌、鳞状上皮细胞癌、肾癌、尿道癌、支气管癌、食管癌、骨癌、咽喉癌、膀胱癌、甲状腺癌、肝癌、头颈癌、眼癌、皮肤癌、口腔癌、胃癌、结肠癌、直肠癌、脑癌和中枢神经系统癌症。
本发明的第五个目的是提供一种制备或开发用于治疗免疫性疾病的药物，所述药物中包含上述通式(I)所示的化合物或其药学上可接受的盐。
所述免疫性疾病选自多发性硬化、中枢神经系统损伤、炎性肠病、类风湿性关节炎、骨关节炎、银屑病、系统性红斑狼疮、移植物抗宿主疾病、哮喘和慢性阻塞性肺疾病。
所述药物的剂型包括传统剂型，例如汤剂、丸剂、散剂、膏剂、丹剂、酒剂、糖浆剂、浸膏剂、锭剂、棒剂、栓剂、曲剂、炙剂等；还包括现代剂型，例如片剂、冲剂、袋泡剂、口服液剂、胶囊剂、滴丸剂、合剂、酊剂、气雾剂、膜剂、针剂、注射剂等。
所述药物还含有其他医学上可接受的辅料，包括黏合剂、填充剂、崩解剂、润滑剂、抗氧剂、矫味剂、芳香剂、助溶剂、乳化剂、增溶剂、渗透压调节剂、着色剂等。
本发明提供的技术方案具有如下优点：
(1)本发明通式I所示结构的化合物或其药学上可接受的盐可用于制备脂肪酸合成酶抑制剂，能够抑制FASN的酶活性，是一种新型的FASN抑制剂。FASN作为细胞脂质代谢中主要的一种酶，参与了肿瘤的发生和发展。FASN在控制肿瘤细胞能量代谢、细胞周期调节、上皮间质转化等方面起着重要作用，有望成为肿瘤诊断的标志物和治疗靶点。FASN抑制剂通过抑制肿瘤细胞内源性脂肪酸的生物合成从而有效控制癌症的发生、发展。因此，本发明脂肪酸合成酶抑制剂对FASN的酶活性抑制效果明显，能够使肿瘤细胞的生长周期停滞在间期，组织肿瘤细胞分裂，抑制肿瘤细胞增殖，促进肿瘤细胞凋亡，发挥对肿瘤的治疗效果，具有重要的临床应用前景。
(2)本发明脂肪酸合成酶抑制剂能够调节脂肪酸组成和比例，可应用于治疗脂肪酸代谢类疾病或者免疫系统疾病。
(3)本发明脂肪酸合成酶抑制剂制备的药物组合物，对脂肪酸酶的抑制效果明显，能够使肿瘤细胞发生细胞周期停滞、并明显缩小活体小鼠内体的移植瘤，抑制脂滴的形成。因此，上述的药物组合物是一种重要的肿瘤治疗前景药物，为癌症或脂肪酸代谢疾病提供了一种新的治疗途径。
图1为式Ⅰ所示化合物对前列腺癌细胞PC3FASN表达的影响；
图2为式Ⅰ所示化合物对多种肿瘤细胞增殖的影响；
图3为式Ⅰ所示化合物对前列腺癌细胞PC3生长周期的影响；
图4为式Ⅰ所示化合物对前列腺癌细胞PC3分裂的影响；
图5为式Ⅰ所示化合物对多种癌细胞脂肪酸组成的而影响；
图6为式Ⅰ所示化合物对前脂肪细胞op9脂滴合成的影响；
图7为式Ⅰ所示化合物对线虫脂滴积累的影响；
图8为式Ⅰ所示化合物对小鼠前列腺癌细胞PC3移植瘤的影响；
图9为式Ⅰ-1所示脂肪酸合成酶抑制剂的核磁氢谱图。
实施例1式I-1化合物的合成
具体合成方法如下：
(1)合成中间体1化合物5-(4-溴苯基氨基)-5-羰基戊酸：
向100mL单口瓶加入5-乙氧基-5-羰基戊酸(2g，12.5mM)，二氯甲烷(30mL)中，冰浴降温至0℃缓慢加入二氯亚砜(3g，25mM)，升至室温后加热回流。反应液猝灭，旋干得到1g中间体1产物，产率为44.9％；
(2)合成中间体2化合物5-(4-溴苯基氨基)-5-羰基戊酸乙酯：
向100mL单口瓶中加入对溴苯胺(1.15g,6.7mmol)，二氯甲烷(15mL)，三乙胺(0.85g，8.4mmol)，降温至0℃，慢慢滴加中间体1(1g,5.6mmol)室温搅拌过夜，TLC显示反应结束，将反应液依次用烯盐酸(15mL)，碳酸氢钠水溶液(15mL)洗涤，无水硫酸钠干燥，过滤，减压蒸馏后得1.2g中间体2，产率：68％。
(3)合成中间体3化合物N-(4-溴苯基)-5-肼基-5-羰基戊酰胺：
向20mL投库瓶中加入中间体2(0.5g，1.6mmol)，水合肼(80％，0.6g，9.5mmol)，乙醇(5mL)，加热90℃回流2hr。TLC显示反应结束，减压蒸除溶剂，硅胶柱层析(石油醚:乙酸乙酯＝100:1～3:1)，得到0.4g中间体3，产率83％。
(4)合成化合物I-1：
向20mL投库瓶中加入中间体3(0.4g,1.3mmol)，5-溴-2-羟基苯甲醛(04g,1.95mmol)，氢氧化钠(0.52g,13mmol)，甲醇(5mL)，室温搅拌3天。将反应液过滤，旋干，得到粗产品，用DMF打浆，得到0.5g产品，产率为80％。
1H-NMR(DMSO,400MHz)δ：1.85(t,2H),2.27(d,1H),2.35(t,2H),2.64(t,1H),6.83(m,1H),7.40(m,2H),7.54(m,2H),7.23(d,1H),10.03(d,2H),10.34(s,1H),11.24(d,1H),11.69(s,1H).质谱(MS+)：482,483m/z:[M+1,M+2]。
实施例2式I-2化合物的合成
(1)合成4-((叔丁氧羰基)氨基)丁酸：
向100mL单口瓶中加入4-氨基丁酸(2g,19.4mmol,1.0eq)，THF(15mL)，水(15mL)，氢氧化钠(1.6g,38.8mmol)，降温至0℃，慢慢滴加(Boc)
2O(5.1g,23.3mmol)，滴完后25℃搅拌12hrs。反应完全后，旋蒸除去THF，加水15mL，乙酸乙酯(10mL)萃取除去过量(Boc)
2O，水相用柠檬酸或烯盐酸调pH至2-3，乙酸乙酯(15mL)萃取，有机相用无水硫酸钠干燥后旋干得3.5g产物，产率为88％。
(2)合成N-(4-溴苯基)-4-((叔丁氧羰基)氨基)丁酰胺：
向100mL单口瓶中加入对溴苯胺(1g,5.8mmol)，二氯甲烷(15mL)，三乙胺(0.76g,7.4mmol)，降温至0℃，慢慢滴加中间体1(1g,5.6mmol)室温搅拌过夜，TLC显示反应结束，将反应液依次用烯盐酸(15mL)，碳酸氢钠水溶液(15mL)洗涤，无水硫酸钠干燥，过滤，减压蒸馏后得1.2g产物N-(4-溴苯基)-4-((叔丁氧羰基)氨基)丁酰胺，产率61％。
(3)合成4-氨基-N-(4-溴苯基)-丁酰胺：
向100mL单口瓶中加入中间体2(0.5g,1.4mmol)，二氯甲烷(5mL)，降温至0℃，慢慢滴加三氟乙酸(1.5mL)，室温搅拌3hrs.TLC显示反应结束，用饱和碳酸氢钠调反应液pH到7，分液，有机相用无水硫酸钠干燥，过滤，旋干得0.25g产物4-氨基-N-(4-溴苯基)-丁酰胺，产率69.4％。
(4)合成化合物I-2：
将三光气(114mg,0.385mmol)溶于二氯甲烷(5mL)，降温至-10℃，慢慢滴加2-甲氧基-5-溴苄胺(238mg,1.1mmol)的二氯甲烷(3mL)溶液，滴完后在-10℃搅拌30min。然后升温至0℃，加入4-氨基-N-(4-溴苯基)-丁酰胺(280mg,1.1mmol)的DCM-THF溶液。加完后室温过夜。TLC显示反应结束，用饱和碳酸氢钠调反应液pH到7，分液，有机相用无水硫酸钠干燥，过滤，旋干后得粗品，硅胶柱层析(石油醚:乙酸乙酯＝100:1到3:1)纯化得0.2g I-2，产率：37％。
1H-NMR(DMSO,400MHz)δ：1.64(m,2H),2.31(t,2H),3.04(t,2H),3.80(s,3H)4.14d,2H),6.16(t,1H),6.26(t,1H),6.91(d,1H),7.22(s,1H),7.36(d,1H),7.40(m,2H),7.62(m,2H),10.11(s,1H)。质谱(MS+)：499，501，m/z:[M+2,M+4]。
实施例3式I-3化合物的合成
化合物I-3的结构如下所示：
将I-2化合物(0.6mmol)溶于二氯甲烷(5mL)中，降温至-20℃,慢慢加入BBr
3(0.9mmol)。然后室温搅拌3小时。TLC显示反应结束。加水(15mL)淬灭，DCM(15mL)萃取，有机相干燥后，有机相用无水硫酸钠干燥，过滤，旋干后得粗品，硅胶柱层析(石油醚:乙酸乙酯＝100:1到3:1)纯化得200mg I-3化合物，产率69％。
1H-NMR(DMSO,400MHz)δ：1.65(m,2H),2.31(t,2H),3.05(t,2H),4.13(d,2H),6.22(t,1H),6.46(t,1H),6.74(t,1H),7.20(m,2H),7.52(m,2H),7.60(m,2H),10.05(s,1H),10.12(s,1H)。质谱(MS+)：485,487，m/z:[M+2,M+4]。
实施例4式I-4化合物的合成
具体合成包括以下步骤：
(1)合成2-甲酰氧基-5-溴苯甲酸：
向50mL单口瓶中加入5-溴2-羟基苯乙酸(4.6mmol)，乙酸酐(9.2mmpl)，滴入一滴浓硫酸。室温反应3hrs。反应完全后，将反应液倒入冰水中，固体析出，过滤干燥得1g产物2-甲酰氧基-5-溴苯甲酸，产率83.3％。
(2)合成2-氯甲酰基苯-4-溴苯甲酸甲酯：
向50mL单口瓶中加入2-甲酰氧基-5-溴苯甲酸(3.86mmol),二氯甲烷(10mL)，降温至0℃，缓慢滴加二氯亚砜(4.64mmol)，回流搅拌2hrs.反应完全后，将反应液旋干得到1g产物2-氯甲酰基苯-4-溴苯甲酸甲酯，产率83.3％。
(3)合成如下中间体4化合物：
向50mL单口瓶中加入实施例1中的中间体3化合物(0.64g,2.12mmol)，四氢呋喃(10 mL)，三乙胺(257mg,2.54mmol)，降温至0℃，缓慢滴加2-氯甲酰基苯-4-溴苯甲酸甲酯(593mg,1.92mmol)的四氢呋喃溶液(6mL)，室温搅拌过夜。反应完全后，加入25mL水，用HCl(1N)调节反应液pH到4，用乙酸乙酯萃取，有机相丢掉。用碳酸钠调节水相pH到9，用乙酸乙酯(3x10mL)，有机相用无水硫酸钠干燥，过滤，旋干得到粗品，粗品用硅胶柱层析(二氯甲烷：甲醇＝100:1到5:1)纯化得763mg中间体4化合物，产率60％。
(4)合成化合物I-4
向50mL单口瓶中加入中间体4(763mg,1.4mmol)，碳酸钾(1g,7.2mmol)，甲醇(10mL)，室温搅拌过夜。反应完全后，过滤反应液，氮气吹干，加入15mL水，用乙酸乙酯(3x10mL)萃取，有机相用无水硫酸钠干燥，过滤，旋干得到粗品，粗品用硅胶柱层析(二氯甲烷：甲醇＝100:1到5:1)纯化得565mg化合物I-4,产率80％。
1H-NMR(DMSO,400MHz)δ：1.81(m,2H),2.25(m,2H),2.44(m,2H),6.85(m,1H),7.48(m,2H),7.53(m,3H),8.01(s,1H),10.05(d,1H),10.32(s,1H),10.5-11.8(1H)。质谱(MS+)：499，501，m/z:[M+2，M+4]。
实施例5式I-5化合物的合成
具体合成包括以下步骤：
(1)合成5-溴2-苄氧基苯乙酸甲酯：
向50mL单口瓶中加入5-溴2-羟基苯乙酸甲酯(1g,4.32mmol)，碳酸钾(1.2g,8.64mmol)，DMF(10mL),室温下搅拌10min，加入苄溴(0.74mg,4.32mmol)。室温搅拌2hrs.TLC显示反应完全。20mL水加入反应液中，用1n盐酸调节pH值到4，用乙酸乙酯(2x10mL)萃取，有机相丢弃。水相用碳酸钠调节pH值至8，用乙酸乙酯(3x10mL)萃取，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，旋干得到1.1g产物5-溴2-苄氧基苯乙酸甲酯，产率80％。
(2)合成5-溴2-苄氧基苯甲醇：
向50mL单口瓶中加入中间体1(1.1g,3.4mmol),THF(11mL)，LiOH水溶液(5mL)。室温搅拌过夜.TLC显示反应完全。将反应液中的THF溶液旋干，水相用乙酸乙酯洗涤，调节pH值到2-3，过滤干燥得到0.84g产物5-溴2-苄氧基苯甲醇，产率80％。
(3)合成5-溴2-苄氧基氯甲基苯：
向50mL单口瓶中加入5-溴2-苄氧基苯甲醇(1g,3.86mmol),二氯甲烷(10mL)，降温至0℃，缓慢滴加二氯亚砜(560mg,4.64mmol)，回流搅拌2hrs.反应完全后，将反应液旋干得到0.76g g产物5-溴2-苄氧基氯甲基苯，产率85％。
(4)合成化合物I-5：
向50mL单口瓶中加入实施例1中的中间体3(0.7g，2.58mmol)，四氢呋喃(10mL)，三乙胺(257mg，2.54mmol)，降温至0℃，缓慢滴加5-溴2-苄氧基氯甲基苯(0.76g,2.34mmol)的四氢呋喃溶液(8mL)。室温搅拌过夜。反应完全后，加入25mL水，用HCl(1n)调节反应液pH到4，用乙酸乙酯萃取，有机相丢掉。用碳酸钠调节水相pH到9，用乙酸乙酯(3x10mL)，有机相用无水硫酸钠干燥，过滤，旋干得到粗品，粗品用硅胶柱层析(二氯甲烷：甲醇＝100:1到5:1)纯化得1.03g I-5，产率：75％。
1H-NMR(DMSO,400MHz)δ：1.86(m,2H),2.25(m,2H),2.37(m,2H),5.27(s,2H),7.10 (m,1H),7.38(m,1H),7.45(m,2H),7.50(m,4H),7.59(m,2H),7.64(m,1H),,7.70(m,1H),10.07(s,2H),10.14(s,1H)。质谱(MS+)：589，591，m/z:[M+2，M+4]。
实施例6式I-6化合物的合成
具体合成包括以下步骤：
(1)合成4-羰基-4-(苯基胺基)丁酸甲酯：
向250ml三口瓶中加入对5.8mmol苯胺和8.4mmol 2-氢-3氢-吡喃-2,6-二酮(cas号108-55-4)，在15mL有机溶剂AcOH存在下，合成中间体5-(4-溴苯基氨基)-5-羰基戊酸。在0～20℃的温度下，生产中间体1，反应产率为80％。
(2)合成4-羰基-4-(苯基胺基)丁酸：
向50ml的烧瓶中加入甲醇20ml，4-羰基-4-(苯基胺基)丁酸甲酯(1g)，NaOH(0.8g),于70下加热回流5h，移置室温下冷却，加入1M稀盐酸调节Ph至4，用乙酸乙酯萃取，分离干燥有机相，减压浓缩，即得4-羰基-4-(苯基胺基)丁酸。
(3)合4-羰基-4-(苯基胺基)丁酰胺：
向50ml的烧瓶中加入DMF 20ml，4-羰基-4-(苯基胺基)丁酸(0.5g)，HOBT(0.3g)，EDC(0.3g)，于室温下搅拌5h，加入氯化铵(0.25g)，于室温下搅拌24h，加入20ml水，用乙酸乙酯萃取，分离干燥有机相，减压浓缩，得到4-羰基-4-(苯基胺基)丁酰胺产品。
(4)合成式I-6化合物：
向20mL投库瓶中加入4-羰基-4-(苯基胺基)丁酰胺(1.3mmol)，苯甲醛(1.95mmol)，氢氧化钠(0.52g,13mmol)，甲醇(5mL)，室温搅拌3天。将反应液过滤，旋干，得到粗产品，用DMF打浆，得到0.3g产品，产率为85％。所得产品的核磁氢谱数据如下：
1H-NMR(DMSO,400MHz)δ：2.60(t,2H)，2.78(t,2H)，7.07(t,1H)，7.30(t,2H)，7.55(t,2H)，7.56(d,2H)，7.76(d,2H)，9.24(s,1H)，9.97(s,1H).
实施例7式I-7化合物的合成
具体合成步骤参照实施例6，将步骤(4)中的苯甲醛替换为苯甲酰氯，得到I-7化合物的。产率81％。
1H-NMR(DMSO,400MHz)δ：2.55(t,2H),2.60(t,2H),7.07(t,1H),7.30(t,2H),7.55(t,2H),7.56(d,2H),7.99(d,2H),9.97(s,1H),11.69(s,1H).
实施例8式I-8化合物的合成
具体合成步骤参照实施例6，仅将步骤(4)中的苯甲醛替换为苯乙醛。产率83％。
1H-NMR(DMSO,400MHz)δ：2.60(t,2H),2.78(t,2H),3.39(s,2H),7.07(t,1H),7.22(t,1H),7.24(d,2H),7.27(t,2H),7.30(t,2H),7.56(d,2H),8.50(t,1H),9.91(s,1H)
实施例9式I-9化合物的合成
向100ml单口瓶中加入脲，加入13.5mmol 4-羰基-4-(苯基胺基)丁酰氯、1.5g NaOH，将瓶口密封，反应时间1h，再加入6.8mmol苯甲酰氯，反应1h。反应液中加入20ml水，用乙酸乙酯萃取，干燥有机相，减压蒸干，粗品通过柱层析得到最终产物，产率83％。
1H-NMR(DMSO,400MHz)δ：2.55(t,2H),2.60(t,2H),7.07(t,1H),7.30(t,2H),7.55(t,2H),7.56(d,2H),7.99(d,2H),9.97(s,1H),10.91(s,2H)。
实施例10式I-10化合物的合成
具体合成步骤参照实施例6，仅将步骤(4)中的苯甲醛替换为2-羟基-5-溴苯乙醛，产率84％。
1H-NMR(DMSO,400MHz)δ：2.60(t,2H),2.78(t,2H),6.81(d,1H),7.38(d,1H),7.52(d,4H),7.59(s,1H),9.24(s,1H),9.97(s,1H),12.72(s,1H)。
实施例11式I-11化合物的合成
向100ml单口瓶中加入6.7mmol 4-((4-溴苯基)胺基)-4-羰基丁酰氯，加入8.4mmol 5-溴-2-羟基苯(甲)酰胺、0.85g三乙胺，反应液中加入20ml水，用乙酸乙酯萃取，干燥有机相，减压蒸干，粗品通过柱层析得到最终产物式I-11化合物。得率83％。
1H-NMR(DMSO,400MHz)δ：2.55(t,2H),2.60(t,2H),6.88(d,1H),7.52(d,4H),7.66(d,1H),8.00(s,2H),9.97(s,1H),11.11(s,1H),11.69(s,1H)。
实施例12式I-12化合物的合成
向100ml单口瓶中加入2.2mmol N-(4-溴苯基)-5-肼基-5-羰基戊酰胺，加入13mmol 5-溴-2-羟基苯乙醛、1.5g NaOH，将瓶口密封，反应时间3天，产物过滤，减压蒸干，得到最终产物。得率83％。
1H-NMR(DMSO,400MHz)δ：2.60(t,2H),2.78(t,2H),3.39(d,2H),7.25(d,1H),7.43(s,1H),7.52(d,4H),8.50(t,1H),9.68(s,1H),9.97(s,1H)。
实施例13式I-13化合物的合成
化合物I-13的合成步骤同化合物I-9，仅将苯甲酰氯替换为2-羟基-5-溴苯甲酰氯，得到化合物I-13化合物，产率81％。
1H-NMR(DMSO,400MHz)δ：2.55(t,2H),2.60(t,2H),6.88(d,1H),7.52(d,4H),7.66(d,1H),8.00(s,1H),8.92(d,2H),9.97(s,1H),10.91(s,1H),11.11(s,1H),11.77(s,1H)。
实施例14式I-1化合物4的制备
向100ml单口瓶中加入1.9mmol N-(4-溴苯基)-5-肼基-5-羰基戊酰胺，加入4.32mmol 5-溴-2-羟基苯(甲)醛、3g NaOH，将瓶口密封，反应时间3天，产物过滤，减压蒸干，得到最终产物,得率73％。
1H-NMR(DMSO,400MHz)δ：2.13(m,2H),2.34(t,2H),2.39(t,2H),6.90(d,1H),7.38(d,1H),7.52(d,4H),7.80(s,1H),8.78(s,1H),10.05(s,1H),11.07(s,1H),11.19(s,1H)。
实施例15
向100ml单口瓶中加入1mmol化合物I-3、1.92mmol三乙胺，冰浴下加入2.16mmol苄溴，室温搅拌2h，产物过滤，减压蒸干，得到最终产物，得率85％。
1H-NMR(DMSO,400MHz)δ：2.01(m,2H),2.44(t,2H),3.38(t,2H),4.43(d,2H),5.18(m,2H),6.02(s,2H),6.86(m,1H),7.19(m.1H),7.35(m,4H),7.48(m,2H),7.56(m,2H),7.87(m,1H),7.70(m,2H)。
实施例16
检测下述式I-1所示的化合物对结肠癌细胞HCT116中FASN活性的影响：
FASN酶活检测：
(1)收集对数期细胞，调整细胞悬液浓度，以直径6cm规格的培养皿每2x10
6个细胞/皿为宜。
(2)在5％CO
2，37℃下孵育，待细胞贴壁完全后弃去原培养基，每皿细胞中分别加入6ml含20μM化合物I-1的1％FBS培养基，以加入6ml含20μM浅蓝菌素的1％FBS培养基作为阳性对照。
(3)孵育4h后弃上清，胰酶消化2min，以2～4倍胰酶体积的完全培养基终止消化，1000rpm离心5min，弃上清，5ml DPBS重悬细胞，取500μl至1.5ml EP管中待蛋白定量，其余离心弃尽上清。
(4)以1ml 10mM KH
2PO
4/KOH pH6.5的缓冲液(含4mM DTT，0.3mg/ml BSA，2.5Mm EDTA)重悬细胞，加入NADPH、乙酰辅酶A和丙二酰辅酶A使其终浓度分别为0.14mM、0.18mM和0.09mM，在340nm处测其吸光度值，测定时间为1min。
FASN酶活的定义：活性单位定义：37℃中每毫克蛋白每分钟氧化1μmol NADPH为 1U；
FASN(U/mg蛋白)＝[(ΔA
测定管-ΔA
空白管)]÷ε÷d×V
总×10
6]÷(Cpr×V
样)÷T＝1.16×(ΔA
测定
管-ΔA
空白管)÷Cpr；
抑制剂对FASN酶活的影响(抑制率)定义为：FASN(％)＝[1-(FASN
抑制剂÷FASN
对照)]×100％；
其中ε：NADPH摩尔消光系数，6.22×10
3l/mol/cm；d：比色皿光径，1cm；V
总：反应体系总体积，1000μL＝0.001L；Cpr：上清液蛋白浓度，mg/ml；V样：加入反应体系中上清液体积，100μl＝0.1ml；T：反应时间，1min；FASN
抑制剂：经各抑制剂处理的细胞FASN酶活；FASN
对照：未经抑制剂处理的细胞FASN酶活。
IC50值测定：
IC50(halfmaximal inhibitory concentration)是指被测量的拮抗剂的半抑制浓度。它能指示一定浓度的某一药物或者物质(抑制剂)诱导肿瘤细胞凋亡50％，该浓度称为50％抑制浓度，即凋亡细胞与全部细胞数之比等于50％时所对应的浓度。IC50值可以用来衡量药物诱导凋亡的能力，即诱导能力越强，该数值越低，也可以反向说明某种细胞对药物的耐受程度。
(1)收集对数期细胞，调整细胞悬液浓度，以96孔板每孔100μl为宜，种板使待测细胞密度调整至1000～10000个/孔，边缘孔以无菌PBS填充。
(2)5％的CO2，37℃孵育细胞，待细胞贴壁完全后弃去原培养基，每孔加入200μl含0.01μM、0.1μM，1μM，5μM和10μM化合物I-1或浅蓝菌素(Cerulenin)的1wt％FBS培养基，复孔数为6。加入等体积DMSO作为阴性对照。
(3)孵育72h后，拍照记录细胞状态，并弃去原培养液，每孔加入100μl含0.5mg/ml MTT(3-(4,5-二甲基噻唑-2)-2,5-二苯基四氮唑溴盐，商品名：噻唑蓝)的无血清培养基.
(4)孵育2～4h后，弃去原培养液，每孔加入150μl二甲亚砜(DMSO)，300rpm振荡10min，使紫色结晶物充分溶解。
(5)在酶联免疫检测仪在OD
570nm处测量各孔的吸光值，并以OD
630nm处吸光值为参考，进行双波长测定，存活率结果经如下公式计算得到：
细胞存活率＝(OD
570-OD
630)/(OD
570阴性对照-OD
630阴性对照)；
其中，OD
570：各处理组OD
570值；OD
630：各处理组OD
630值；OD
570对照：阴性对照组的OD
570值；OD
630对照：阴性对照组的OD
630值。
(6)按浓度梯度将存活率结果用graphpad6.0软件处理，分析模式为log(inhibitor)vs.Nonlinear regression(curve fit)，计算所得IC50值表述为x±SD。
FASN表达量检测：
Western-blot检测以上述以化合物I-1处理的结肠癌细胞HCT116中FASN蛋白表达量的变化，以浅蓝菌素处理的结肠癌细胞中蛋白表达变化量作为阳性对照。Western-blot具体步骤如下：
A.配制溶液：
(1)10％(w/v)十二烷基硫酸钠SDS溶液：0.1gSDS，1mL的H
2O去离子水配制，室温保存。
(2)分离胶缓冲液：称取18.15g的Tris，用80ml水溶解后，用HCl调节pH到8.8，加水稀释到100mL终体积，得到1.5mmol/L的Tris-HCl(pH8.8)溶液。
(3)浓缩胶缓冲液：6.05gTris溶于80mL水中，用约HCI调至pH6.8，加水稀释到100ml终体积，得到0.5mmol/L的Tris-HCl(pH6.8)溶液。
(4)SDS-PAGE加样缓冲液：将pH6.8的0.5mol/L的Tris缓冲液8mL，甘油6.4mL，10wt％的SDS 12.8mL，巯基乙醇3.2mL，0.05wt％的溴酚蓝1.6mL，H
2O 32mL混匀备用。
(5)Tris-甘氨酸电泳缓冲液：称取30.3gTris、188g甘氨酸和10g SDS，用蒸馏水溶 解至1000ml，临用前稀释10倍。
(6)转膜缓冲液：称取14.4g甘氨酸、6.04g Tris，向其中加入200ml甲醇，最后加水至总体积为1l。
(7)Tris缓冲盐溶液(TBS)：含有20mM的Tris-HCl(pH7.5)和500mM的NaCl。
B.将癌细胞用PBS清洗3次，加入裂解液，直接煮沸5分钟，冰上冷却后，12000rpm离心2min，取上清，-20℃保存备用。
C.采用BCA法测定蛋白质浓度。
将0.5mg/ml标准蛋白梯度加到孔板中，加PBS补足至20μl；加适当体积(3μl)蛋白质样品到孔板中，加PBS补足至20μl；各孔加入200μl BCA工作液(使用前配制，现配现用)，37℃孵育30min；测定波长562nm吸光度，通过标准曲线和样品体积计算出蛋白质的浓度。
D.SDS-PAGE凝胶电泳
(1)清洗后的两块玻璃板对齐后放入夹中卡紧，然后垂直卡在架子上准备灌胶。
(2)灌注10wt％分离胶：分离胶缓冲液中加入TEMED(四甲基乙二胺)后立即摇匀，灌注至两块玻璃板中间的间隙内，随即用乙醇液封，胶充分凝固就可倒去胶上层乙醇并用吸水纸吸干。
(3)灌注5wt％的浓缩胶：浓缩胶缓冲液中加入TEMED(四甲基乙二胺)后立即摇匀，灌注至分离胶的上层，将剩余空间灌满浓缩胶然后将梳子插入浓缩胶中。待到浓缩胶凝固后，竖直向上轻轻将其拔出。
(4)将灌胶完成后的玻璃板放入电泳槽中，加足够的电泳液后开始准备上样。蛋白质样品测完蛋白含量后，加入5×SDS上样缓冲液，在沸水中煮3min混匀后上样，上样的总蛋白量为35μg。
(5)恒压80V电泳跑胶，当样品进入下层胶后恒压120V电泳直至溴酚蓝达到凝胶底部为止，进行转膜。
E.转膜
(1)切胶：将玻璃板撬掉，除去小玻璃板后，将浓缩胶刮去，根据实验需要按照蛋白的分子量，以Marker为对照进行切胶。
(2)备膜：裁剪PVDF膜和滤纸，将切好的PVDF置于80％甲醇溶液中激活30s。
(3)装膜：将转膜用的夹子打开使黑的一面(负极)保持水平。在上面垫一张海绵垫，加入转膜液浸湿，在垫子上垫上中浸泡好的滤纸，随后按照凝胶—硝酸纤维素膜—滤纸—海绵垫的顺序依次叠放。最后将白色板(正极)盖好装入转膜槽中。
(4)转膜：将夹子放入转移槽槽中，要使夹的黑面对槽的黑面，夹的白面对槽的红面。4℃转膜，恒流400mA。
(5)转完后将膜取下，标记一角。
F.免疫反应
(1)封闭：将膜用TBST中漂洗3次，每次5min。漂洗后将硝酸纤维素膜放入5％脱脂奶粉中，室温下摇床1h。
(2)加一抗(FASN)：将封闭后的硝酸纤维素膜放入含有TBST的洗缸中摇床上漂洗3次，每次5min。放入加有一抗的平皿中4℃过夜孵育。
(3)加二抗(鼠抗或兔抗)：回收一抗，将硝酸纤维素膜在TBST洗缸中室温摇床漂洗3次，每次5min，然后将漂洗过的硝酸纤维素膜放入加有二抗的平皿中，避光室温孵育45min。孵育后将硝酸纤维素膜在TBST洗缸中洗3次，每次5min。
G.化学发光
将显色试剂在小离心管里按照发光试剂盒说明书操作将其混合，加到硝酸纤维素膜上，用化学发光成像仪显色。
表1显示化合物I-1至I-8和两种中间产物对结肠癌细胞HCT116中脂肪酸合成酶 FASN活性的影响结果，与对照组相比，多种化合物和浅蓝菌素均能降低结肠癌细胞中的FASN活性，且与浅蓝菌素相比，化合物I-1至I-8的抑制效果明显高于浅蓝菌素。
图1显示化合物I-1至I-8对结肠癌细胞HCT116中FASN表达变化量的影响，结果显示无论加入化合物I-1至I-8还是浅蓝菌素对FASN的表达量未发生明显变化，说明化合物I-1至I-8能够抑制FASN的酶活性，但不影响FASN的正常表达。
上述结果说明式I-1至I-8所示的化合物能够作为一种新型的脂肪酸合成酶抑制剂，形成对FASN的有效抑制。提示式I-1所示的化合物能够作为肿瘤、肥胖等相关代谢疾病的治疗药物，预防和/或治疗疾病的发生、发展。
实施例17
检测式I-1所示的化合物对肿瘤细胞(22RV1、PC-3、HT-29、Hela、Hep G2和CaCo-2)增殖的影响：
(1)收集对数期细胞，调整细胞悬液浓度，以96孔板每孔100μl为宜，种板使待测细胞密度调整至1000～10000个/孔，边缘孔以无菌PBS填充。
(2)5％的CO2，37℃孵育细胞，待细胞贴壁完全后弃去原培养基，每孔加入200μl含10μM化合物I-1的1wt％FBS培养基，复孔数为6。分别加入相同浓度的脂肪酸合成酶抑制剂C75、浅蓝菌素(Cerulenin)和GSK2194069(以下表示为GSK)作为阳性对照，加入等体积DMSO作为阴性对照。
(3)孵育72h后，拍照记录细胞状态，并弃去原培养液，每孔加入100μl含0.5mg/ml MTT(3-(4,5-二甲基噻唑-2)-2,5-二苯基四氮唑溴盐，商品名：噻唑蓝)的无血清培养基.
(4)孵育2～4h后，弃去原培养液，每孔加入150μl二甲亚砜(DMSO)，300rpm振荡10min，使紫色结晶物充分溶解。
(5)在酶联免疫检测仪在OD
570nm处测量各孔的吸光值，并以OD
630nm处吸光值为参考，进行双波长测定，结果经如下公式计算得到：
细胞存活率＝(OD
570-OD
630)/(OD
570阴性对照-OD
630阴性对照)；
其中，OD
570：各处理组OD
570值；OD
630：各处理组OD
630值；OD
570对照：阴性对照组的OD
570值；OD
630对照：阴性对照组的OD
630值。
图2显示脂肪酸合成酶抑制剂C75、浅蓝菌素和GSK，以及化合物I-1对22RV1、PC-3、HT-29、Hela、Hep G2、CaCo-2和HCT116共7种不同肿瘤细胞的增殖的影响。由图2可知虽然C75、浅蓝菌素和GSK作为脂肪酸合成酶抑制剂，具有抑制肿瘤细胞增殖的效果，但在不同种类的肿瘤细胞中效果相差较大，对部分肿瘤细胞的增殖无明显影响，稳定性差。与上述三种抑制剂相比，化合物I-1对肿瘤增殖的抑制效果明显提升，且对多种不同种类的肿瘤细胞中均能形成有效抑制。
实施例18
检测式I-1所示的化合物对前列腺癌细胞PC-3生长周期的影响：
(1)取处于对数生长期的癌细胞，接种于6cm培养皿中，每皿接种量为2x10
6个细胞，5％CO
2，37℃孵育。
(2)待细胞贴壁完全后，无血清饥饿12h，加入6ml含不同浓度梯度(4μM、8μM和10μM)的式Ⅰ所示的结构化合物的2％FBS培养基。
(3)孵育24h后，弃上清，胰酶消化2min，以2～4倍胰酶体积的完全培养基终止消化，1000rpm离心5min，弃上清，1ml DPBS洗两次，弃尽上清。
(4)1ml 70％乙醇溶液重悬细胞，4℃贮存18h以上以固定细胞。
(5)离心弃上清，DPBS洗两次以清除残留乙醇。
(6)离心弃上清，1ml PI染液室温避光孵育15min，1h内流式细胞仪上机检测。
图3为不同浓度的式Ⅰ所示的结构化合物对前列腺癌细胞PC-3生长周期的影响。图3显示未经抑制剂处理的对照组的前列腺癌细胞PC-3，和分别经4μM、6μM、8μM和10μM化合物I-1处理后的前列腺癌细胞PC-3分别处于的G0/G1期、S期(S-Phase)和G2/M 期的比例关系的统计结果图。由图3可知，经式Ⅰ所示的结构化合物处理的PC3细胞S期细胞所占比例明显增多，从对照组的10.34％增加至10μM处理组的19.10％，从而使进入分裂期(M期)和G0/G1期的肿瘤细胞的比例下降，对前列腺癌细胞PC3的有丝分裂进行抑制，呈现S期周期阻滞，且随药物浓度的增加，阻滞情况明显增加。
因此，式Ⅰ所示的结构化合物可导致PC-3出现明显的S期周期，抑制肿瘤细胞的增殖，促进肿瘤细胞的凋亡，且该化合物对肿瘤细胞生长周期的阻滞呈现浓度依赖性。提示式Ⅰ所示的结构的化合物能够抑制肿瘤的发生、发展，作为一种新型的治疗药物应用于肿瘤的临床治疗。
实施例19
检测式I-1所示的化合物对前列腺癌细胞PC3细胞分裂的影响：
(1)取处于对数生长期的癌细胞，弃培养基，胰酶消化2min，以2～4倍胰酶体积的完全培养基终止消化，1000rpm离心5min，弃上清。
(2)1ml无血清培养基洗一次，离心弃尽上清。
(3)4ml无血清培养基重悬细胞，并计数。
(4)1:1(v:v)加入10μm CFSE工作也，37℃避光孵育15min。
(5)加入血清使其终浓度为40％，冰上孵育10min终止染色。
(6)离心弃上清，以完全培养基重悬细胞，并接种于6cm培养皿中，每皿接种量为2x10
6个细胞，5％CO
2，37℃孵育。
(7)待细胞贴壁完全后，加入6ml含10μM式Ⅰ所示的结构化合物的2％FBS培养基。
(8)孵育24h后，弃培养基，胰酶消化2min，以2～4倍胰酶体积完全培养基终止消化，1000rpm离心5min，弃上清，1ml DPBS重悬细胞，流式细胞仪上机检测。
图4为式Ⅰ所示的结构的化合物对前列腺癌细胞PC-3细胞分裂的影响，由图可知，与未添加化合物I-1的相比，经式Ⅰ所示结构的化合物处理的前列腺癌细PC3的分裂峰数量明显减少，说明该化合物可以有效抑制细胞分裂，减少细胞分裂次数，进而影响癌细胞的生长，对肿瘤增殖起到抑制效果。提示式Ⅰ-1所示的结构的化合物能够抑制肿瘤的发生、发展，作为一种新型的治疗药物应用于肿瘤的临床治疗。
实施例20
检测式I-1所示结构的化合物对肿瘤细胞(前列腺癌细胞PC-3和结肠癌癌细胞HCT116)合成的脂肪酸含量和组成的影响：
(1)取处于对数生长期的癌细胞，于6cm细胞培养皿种板，种板密度为2x10
6个细胞，5％CO
2，37℃孵育。
(2)待细胞贴壁后，每皿加入6ml含20μM式Ⅰ所示化合物的1％FBS培养基，以培养基为阴性对照，以浅蓝菌素为阳性对照。
(3)孵育24h后，弃培养基，胰酶消化2min，以2～4倍胰酶体积完全培养基终止消化，1000rpm离心5min，弃上清。
(4)10ml DPBS重悬，取1ml细胞悬液至1.5ml ep管中用于蛋白定量，其余9ml再次离心弃上清，加入适量体积内标，冻干。
(5)加入1ml 0.5M NaOH-甲醇溶液，充氮，涡旋振荡30s，100℃固浴5min，冷却至室温。
(6)加入1ml 40％三氟化硼-甲醇溶液，充氮，涡旋振荡30s，100℃固浴5min，冷却至室温。
(7)加入4ml正己烷，2ml饱和氯化钠溶液，涡旋振荡，2000rpm离心10min，取上清，氮吹至完全，500μl正己烷重悬，转移至进样瓶中，气质联用上机检测。
图5为式Ⅰ所示化合物对前列腺癌细胞PC-3和结肠癌细胞HCT116脂肪酸含量和组成的影响，脂肪酸种类包括18:2、18:1、18:0、16:1、16:0和14:0。由图5可知，经式Ⅰ 所示化合物处理的PC-3和HCT116细胞脂肪酸总量明显低于对照组，且16:0的脂肪酸含量也低于对照组，说明式Ⅰ所示化合物能够抑制PC-3和HCT116中脂肪酸的合成，改变肿瘤细胞内的脂肪酸的分布，从而影响肿瘤细胞的新陈代谢。抑制脂肪酸的合成使提供细胞增殖所需的结构脂质和能量减少，是抑制肿瘤增殖、造成肿瘤细胞凋亡的重要原因，因此，化合物I-1能够抑制肿瘤的发生、发展，具有重要的临床应用前景。
实施例21
检测式I-1所示结构的化合物对前脂肪细胞OP9的影响：
(1)取处于对数生长期的癌细胞，于6cm细胞培养皿种板，种板密度为2x10
6个细胞，5％CO
2，37℃孵育。
(2)待细胞贴壁后，每皿加入6ml含20μM式Ⅰ所示化合物的1％FBS培养基，以培养基为阴性对照，以浅蓝菌素为阳性对照。
(3)孵育24h后，弃培养基，胰酶消化2min，以2～4倍胰酶体积完全培养基终止消化，1000rpm离心5min，弃上清。
(4)10ml DPBS重悬，取1ml细胞悬液至1.5ml ep管中用于蛋白定量，其余9ml再次离心弃上清，加入适量体积内标，冻干。
(5)加入1ml 0.5M NaOH-甲醇溶液，充氮，涡旋振荡30s，100℃固浴5min，冷却至室温。
(6)加入1ml 40％三氟化硼-甲醇溶液，充氮，涡旋振荡30s，100℃固浴5min，冷却至室温。
(7)加入4ml正己烷，2ml饱和氯化钠溶液，涡旋振荡，2000rpm离心10min，取上清，氮吹至完全，500μl正己烷重悬，转移至进样瓶中，气质联用上机检测。
图6A为经式Ⅰ所示结构的化合物处理的op9细胞在显微镜下的脂滴油红染色情况及正己烷溶出后所测得的OD510值。由图6A可以看出，与对照组相比，经式Ⅰ所示结构的化合物处理的OP9细胞脂滴数量显著下降，且下降幅度大于经浅蓝菌素处理的实验组，图6B所得OD
510值也证明了同样的结果，表明式Ⅰ所示结构能够抑制前脂肪细胞OP9中脂滴的积累。
实施例22
检测式Ⅰ所示结构的化合物对线虫体内脂滴积累的影响：
取线虫以M9缓冲液重悬，每只试管中加入3ml线虫悬液，实验组加入式Ⅰ所示化合物使其终浓度为10μM，以不加式Ⅰ所示化合物为对照，200rpm/min摇床振荡培养，9d后进行油红染色，置于载玻片上于显微镜下观察脂滴情况。
图7为经式Ⅰ所示化合物处理9d的线虫体内脂滴积累情况。如图所示，经式Ⅰ所示化合物处理的线虫，油红染色后色泽明显比对照组浅，可看到明显的白色区域，而对照组线虫整体呈现深色，无白色区域，可见，经式Ⅰ所示化合物处理的线虫脂滴积累明显少于对照组，说明式Ⅰ所示化合物可有效抑制线虫脂滴的合成和积累。化合物I-1对脂滴合成和积累的抑制作用，提示其可以在肥胖症等代谢性疾病的治疗过程中发挥效果。
实施例23
检测式Ⅰ所示结构的化合物对小鼠移植瘤生长的影响：
(1)培养癌细胞至密度80％(对数生长期)，按照细胞传代实验进行，PBS洗涤，消化，离心去上清，之后用无血清的培养基重悬洗涤细胞两遍；用无血清培养基调整细胞悬液浓度为2×10
7个/ml；等体积加入已经过夜四度融化的基质胶，振荡混合均匀待用(含基质胶的步骤全部在冰上操作)；
(2)每只裸鼠在背部皮下接种100μl细胞与基质胶混合液，接种后每天定时观察肿瘤的生长情况，确定移植瘤模型是否成功，待肿瘤体积约在200mm
3，开始药物处理；
(3)实验选取移植瘤模型成功裸鼠(成瘤率100％)，裸鼠适应饲养7d，进行皮下癌细胞移植实验，待瘤体肉眼可见后，每隔2d进行一次腹腔注射，注射剂量为5mg/kg 的化合物I-1，以注射溶剂组为对照，每组5只。给药4周后，取瘤体称重(图9A)。
(4)肿瘤体积计算公式：
V＝ab
2/2，式中V为体积(mm
3)，a为长度(mm)，b为宽度(mm)；
(5)将瘤体切片后进行H&E染色，观察小鼠肿瘤组织的变化情况。
图8为经式Ⅰ-1所示化合物对小鼠PC3移植瘤的影响。其中图8A为化合物I-1处理后小鼠肿瘤的质量变化情况，图8B显示化合物I-1处理后移植瘤的HE染色效果。如图8A所示，经式Ⅰ-1所示化合物处理四周的小鼠肿瘤质量明显低于对照组。图8B为肿瘤HE染色切片，可观察到经式Ⅰ所示化合物处理的小鼠肿瘤组织出现了大面积浅色区域，深点点状区域明显减少，表明经式Ⅰ-1所示化合物可以抑制肿瘤细胞增殖，导致肿瘤组织内部大面积水肿。
由上述结果可知，化合物I-1对小鼠肿瘤的抑制效果明显，化合物I-1作为一种新型的抗肿瘤药物具有重要的应用前景。
实施例24
检测化合物I-1～化合物I-8及中间体1和中间体2对HCT116中FASN活性的抑制效果，以及对肿瘤细胞(PC-3和HCT116)增殖的影响。
以实验例18中所示的FASN酶活的测定方法检测不同物质对FASN酶活性的影响，以实验例19中所示的方法检测不同物质对肿瘤细胞增殖增殖的影响，并以浅蓝菌素为对照计算不同物质对FASN酶活性抑制率(％)和对肿瘤增殖的抑制率(IC
50nM)。检测结果如下述表1所示：
表1 不同物质对FASN酶活性和肿瘤增殖的抑制效果
| FASN酶活性抑制率(％) | PC-3(IC 50nM) | HCT116(IC 50nM) | |
| 浅蓝菌素 | 21.32 | 18±2.7 | 29±3.2 |
| 化合物I-1 | 58.63 | 9±1.1 | 13±1.7 |
| 化合物I-2 | 30.73 | 16±2.9 | 21±1.6 |
| 化合物I-3 | 41.22 | 14±2.8 | 15±2.5 |
| 化合物I-4 | 49.02 | 11±1.8 | 14±1.7 |
| 化合物I-5 | 39.17 | 15±2.7 | 18±2.9 |
| 化合物I-6 | 41.87 | 15±1.8 | 17±2.7 |
| 化合物I-7 | 37.67 | 15±2.1 | 19±1.9 |
| 化合物I-8 | 35.22 | 16±1.7 | 20±3.5 |
| 中间体1 | 31.87 | 15±1.3 | 19±2.1 |
| 中间体2 | 22.16 | 18±2.5 | 22±3.1 |
由上述表1可知，本发明提供的化合物I-1至化合物I-8均具能有效抑制脂肪酸合成酶活性，其中以化合物I-1对脂肪酸合成酶(FASN)的抑制率最高，为58.63％，明显高于阳性对照浅蓝菌素的抑制率21.32％；且根据IC50结果可知，化合物I-1有效浓度也明显低于浅蓝菌素，9±1.1nM时可致前列腺癌细胞PC3达到50％的死亡率，而13±1.7nM可致结肠癌细胞HCT116达到50％的死亡率。脂肪酸合成酶(FASN)参与肿瘤脂肪酸代谢和细胞周期过程，在肿瘤的生长、侵袭和迁移中发挥重要作用，本发明提供的具有通式I-1所示结构的化合物，能够作为FASN抑制剂，影响肿瘤细胞中的脂肪酸合成、分布，使细胞周期停滞在间期，组织肿瘤细胞的有丝分裂，实现对肿瘤增殖的抑制。因此，通式I所示结构的化合物作为一种新型的脂肪酸合成酶抑制剂，在肿瘤的临床治疗、以及肥胖症等代谢性疾病的治疗中具有重要的应用前景。
虽然本发明已以较佳实施例公开如上，但其并非用以限定本发明，任何熟悉此技术的人，在不脱离本发明的精神和范围内，都可做各种的改动与修饰，因此本发明的保护范围应该以权利要求书所界定的为准。
Claims (12)
- 通式(I)所示的化合物或其药学上可接受的盐在制备用于抑制脂肪酸合成酶药物中的应用，
其中，为单键或双键；R 1、R 2分别独立地选自羟基、卤素、C1-C4烷基、C1-C4烷氧基中任意一种；
环A为U、V、Z分别独立地选自CH、N、NH；R 3、R 4分别独立地选自氢、卤素、羟基、芳氧基和烷氧基中任意一种，且R 3、R 4不同时为氢；
Q为至少一个杂原子或不包含杂原子的C 1～5直链或支链烃基，所述杂原子分别独立地选自氮、氧和硫；L为酮基或亚胺基；W选自-(CH 2) a、-(CH 2) a-C(O)-、-(CH 2) a-OC(O)-、-(CH 2) n-C(O)O-中任意一种，其中a为0-3的自然数；X选自-N(R) mN(R) n-、-C(O)N(R) n-或-N(R) nC(O)-，m和n分别独立地为0或1；R独立地为氢、卤素或苯基；Y选自氮、氧或硫。 - 根据权利要求1所述的应用，其特征在于，所述通式(I)中环A的芳环为单环芳基、萘基、[1,8]萘啶基、苯并噁唑基、苯并噻唑基、苯并咪唑基、苯并三唑基、吲哚基、苯并-1,3-二氧杂环戊烯基、苯并二氧杂环己烷基、苯并噻二唑基、吲唑基、苯并呋喃基、喹啉基、异喹啉基、噁唑并[5,4-b]吡啶基或噁唑并[5,4-c]吡啶基。
- 根据权利要求1所述的应用，其特征在于，所述通式(I)中Q选自端基为-N(R)-、-S-、-O-、-SO-、-SO 2-、-NRC(O)-、-C(O)NR-、-N(R)SO 2-、-SO 2N(R)-、-OC(O)-或-C(O)O-的C 1～5直链或支链烃基。
- 根据权利要求2所述的应用，其特征在于，所述通式(I)中Q选自端基为-N(R)-、-S-、-O-、-SO-、-SO 2-、-NRC(O)-、-C(O)NR-、-N(R)SO 2-、-SO 2N(R)-、-OC(O)-或-C(O)O-的C 1～5直链或支链烃基。
- 根据权利要求1-4任一所述的应用，其特征在于，所述通式(I)所示化合物药学上可接受的盐包括：乳酸盐、盐酸盐、磷酸盐、醋酸盐、苹果酸盐、枸椽酸盐或天冬氨酸盐。
- 根据权利要求1-4任一所述的应用，其特征在于，所述通式(I)中W为-CH 2-或-C(O)-。
- 根据权利要求5所述的应用，其特征在于，所述通式(I)中W为-CH 2-或-C(O)-。
- 一种用于抑制脂肪酸合成酶的药物组合物，其特征在于，所述药物组合物包括权利要求1中通式(I)所示的化合物或其药学上可接受的盐。
- 权利要求1中通式(I)所示的化合物或其药学上可接受的盐在制备用于治疗脂肪酸代谢疾病药物中的应用。
- 权利要求1中通式(I)所示的化合物或其药学上可接受的盐在制备用于治疗癌症或者免疫性疾病药物中的应用。
- 根据权利要求1或9或10所述的应用，其特征在于，所述药物的剂型包括汤剂、丸剂、散剂、膏剂、丹剂、酒剂、糖浆剂、浸膏剂、锭剂、棒剂、栓剂、曲剂、炙剂等；还包括现代剂型，例如片剂、冲剂、袋泡剂、口服液剂、胶囊剂、滴丸剂、合剂、酊剂、气雾剂、膜剂、针剂、注射剂。
- 根据权利要求1或9或10所述的应用，其特征在于，所述药物还含有其他医学上可接受的辅料，包括黏合剂、填充剂、崩解剂、润滑剂、抗氧剂、矫味剂、芳香剂、助溶剂、乳化剂、增溶剂、渗透压调节剂、着色剂。
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| EP2019091A1 (en) * | 2007-06-25 | 2009-01-28 | Fundació Privada Institut d'Investigació Biomédica de Girona - Dr. Josep Trueta | Novel polyhydroxylated compounds as Fatty Acid Synthase (FASN) inhibitors |
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| WO1998022432A1 (fr) * | 1996-11-18 | 1998-05-28 | Yamanouchi Pharmaceutical Co., Ltd. | Derives d'acylanilide a substitution acylamino ou composition comprenant ces derives |
| WO1998031689A1 (fr) * | 1997-01-20 | 1998-07-23 | Adir Et Compagnie | Derives d'acides boroniques ou phosphoniques inhibiteurs d'angiogenese |
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