CN112601741A - 用于myc抑制的改进化合物 - Google Patents
用于myc抑制的改进化合物 Download PDFInfo
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- CN112601741A CN112601741A CN201980055350.9A CN201980055350A CN112601741A CN 112601741 A CN112601741 A CN 112601741A CN 201980055350 A CN201980055350 A CN 201980055350A CN 112601741 A CN112601741 A CN 112601741A
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Abstract
公开了化合物、药物组合物以及用改进的Myc抑制剂化合物进行癌症治疗的方法。更具体地,公开了改进的化合物,其具有改善的溶解性、改进的结合特征以及更好的抑制c‑MYC的效力和治疗活性,其中相对于早前公开的三取代吡啶结构类别,所述改进的化合物在R1位置包含具有噻唑基部分的三取代吡啶。
Description
相关申请的交叉引用
本专利申请要求美国临时专利申请号62/695,496(于2018年7月9日提交)的优先权权益。优先权申请的全部公开内容通过引用以其整体并出于所有目的并入本文。
技术领域
本公开内容提供了改进的Myc抑制剂化合物、药物组合物以及用该改进的Myc抑制剂药物组合物治疗癌症的方法。本公开内容提供了活性提高的化合物小类别,其表现出优于公开内容化合物(于2014年12月10日提交的美国专利申请序列号15/035,842,其公开内容通过引用并入本文)的出人意料的改进结果。在先专利申请中以先导物(lead)例示的化合物在本文中称为KJ-Pyr-9。KJ-Pyr-9在鸡胚成纤维细胞(chicken embryo fibroblast,CEF)中表现出对致癌性ATG-MYC病毒转化能力的抑制,并且将那些数据用于与本文中公开的改进化合物进行比较。然而,KJ-Pyr-9(或化合物5a)和先前描述的相关化合物也仅表现出一般的溶解度(约8μM)。因此,本领域需要对先前公开化合物的化学特征进行改进。
背景技术
v-myc髓细胞瘤病毒癌基因同源物(MYC)蛋白是转录物组中占据顶端位置(apicalspace)的细胞周期进程关键调节剂(Adhikary et al.,Nat.Rev.Mol.Cell Biol.2005,6(8),635–645)。原癌基因c-myc编码控制细胞增殖的转录因子(Myc)。Myc在调节细胞周期、细胞生长、血管生成、凋亡和肿瘤生成中也发挥作用。MYC参与几乎所有癌症,并且MYC的功能获得见于几乎所有人癌症中。由于突变、染色体重排、表达提高或基因扩增,Myc的活性可在肿瘤中增高。在广泛的人癌症中已检测到c-Myc表达升高或失调,并且其通常与侵袭性、低分化肿瘤相关。这样的癌症包括结肠癌、乳腺癌、宫颈癌、小细胞肺癌、骨肉瘤、胶质母细胞瘤、黑素瘤和髓样白血病。
研究MYC的部分困难在于其猛烈的(frenetic)作用模式:尽管存在短暂,但其看起来能够以局部和总体方式二者来影响转录。此外,MYC作为固有无序蛋白(intrinsicallydisordered protein,IDP)存在,其仅在存在MAX网络的其他碱性螺旋-环-螺旋亮氨酸拉链(basic helix-loop-helix leucine zipper,bHLH-LZ)转录因子的情况下才形成结构(Conacci-Sorrell et al.,Cold Spring Harb.Perspect Med.2014,4(1),a014357–a014357;以及McKeown and Bradner,Cold Spring Harb.Perspect Med,2014,4(10),a014266)。这种结构缺乏和不稳定性极大地损害了在结构或生物物理上表征MYC相互作用的能力。总之,这些属性使得MYC成为药物发现中有吸引力但难以捉摸的靶标。
发明内容
本公开内容提供了包含式(I)的药物化合物
其中:
X是N或CH;
R1是氰基或噻唑基;
R2是2-呋喃基;
R3是p-C6H4-CONH2。优选地,R1是噻唑基。
本公开内容还提供了包含有效量的式(I)化合物的药物组合物
其中:
X是N或CH;
R1是氰基或噻唑基;
R2是2-呋喃基;
R3是p-C6H4-CONH2。优选地,R1是噻唑基。
本公开内容还提供了用于治疗癌症适应症的方法,其包括施用有效量的包含式(I)的组合物
其中:
X是N或CH;
R1是氰基或噻唑基;
R2是2-呋喃基;
R3是p-C6H4-CONH2。优选地,R1是噻唑基。
或者,本公开内容包含抑制MYC-MAX二聚化的方法,其包括使MYC与有效量或浓度的式(I)化合物接触
其中:
X是N或CH;
R1是氰基或噻唑基;
R2是2-呋喃基;
R3是p-C6H4-CONH2。
更进一步,所公开的方法抑制MYC实现的转录激活,所述方法包括使MYC与有效量或浓度的式(I)化合物接触
其中:
X是N或CH;
R1是氰基或噻唑基;
R2是2-呋喃基;
R3是p-C6H4-CONH2。
在多个实施方案中,本发明还提供了抑制MYC诱导的细胞增殖的方法,其包括使MYC与有效量或浓度的式(I)化合物接触
其中:
X是N或CH;
R1是氰基或噻唑基;
R2是2-呋喃基;
R3是p-C6H4-CONH2。
附图说明
图1示出了受试化合物的活性筛选。(A)与5a相比,与MYC的相对结合。(B)通过SPR测量的对MYC-MAX与DNA结合的抑制。(C)CEF测定中经优化化合物的IC50。
图2示出了通过质量分析获得的大鼠肝微粒体的氧化易感性。将化合物与微粒体在37℃下一起孵育指定时间。根据提取离子的AUC计算回收率。
具体实施方式
通过Krohnke吡啶合成,产生了一系列化合物,以使用两种途径(方案1a、1b)合成α,β-不饱和酮2家族:对于方案(1a),带有多种不同五元杂环(例如噻唑、咪唑和三唑)的甲基酮的反应,或者对于方案(1b),与相应酰氯进行的唑反应,其允许引入唑部分。在100℃下使用乙酸铵进行的α,β-不饱和酮2与吡啶盐1(从相应的苯甲酰甲基溴衍生物获得)之间的第二反应得到相应的2,4,6-三取代吡啶3。这时候,获得化合物5i至k,而其他化合物在R3位置包含对甲酯基。使3的甲酯基水解,以获得羧酸4。使羧酸与草酰氯和N,N-二甲基甲酰胺反应以获得相应的酰氯,然后使其与不同的亲核体反应以形成化合物5。为了获取截短的吡啶支架(例如7a和7b),如方案1b所示,使用了钯催化的Suzuki交叉偶联策略。
在制备这些化合物之后,下一步是检查它们相对于现有技术化合物5a的活性。
方案1a中的基团R1、R2和R3的身份如下:
5a:R1=NO2;R2=2-呋喃基;R3=p-C6H4-CONH2
5b:R1=CN;R2=2-呋喃基;R3=p-C6H4-CONH2
5c:R1=CN;R2=2-噻唑基;R3=p-C6H4-CONH2
5e:R1=CN;R2=N-甲基-2-咪唑基;R3=p-C6H4-CONH2
5f:R1=CN;R2=1-甲基-1H-1,2,3-三唑基-5-基;R3=p-C6H4-CONH2
5g:R1=2-噻唑基;R2=2-呋喃基;R3=p-C6H4-CONH2
5i:R1=CN;R2=2-呋喃基;R3=C6H5
5j:R1=2-噻唑基;R2=2-呋喃基;R3=2-噻唑基
5k:R1=CN;R2=2-呋喃基;R3=p-C6H4-CN4H
5l:R1=CN;R2=2-呋喃基;R3=p-C6H4-CONHMe
5m:R1=CN;R2=2-呋喃基;R3=p-C6H4-CONHSO2Me
5n:R1=CN;R2=2-呋喃基;R3=p-C6H4-CONHNH2
5o:R1=CN;R2=m-C6H4F;R3=p-C6H4-CONH2
方案1a:
方案1b:
化合物溶解度通过动态光散射来测量(表1)。使用了场效应晶体管(Bio-FET)并且其与SPR或等温量热法相比,提供了较低的检测限。2.在石墨烯表面上进行检测。3.使经His标记的bHLH构建体固定在芯片上以进行位点特异性功能化。出人意料地,在缓冲液中用3%DMSO的情况下,在10μM的现有技术先导物5a下大致观察到半最大曲线。将其用作所筛选的每个芯片上的对照,并给出了对蛋白质的溶解度和亲和力二者方面的基准(图1-A栏,表1)。还针对单体形式的MAX(mMAX)以及MYC-MAX和MAX-MAX二聚体对化合物进行了筛选。没有观察到与mMAX、MAX-MAX和未结合的对照表面的结合以及再生芯片表面的一般能力,表明观察到的结合相互作用具有特异性。
MYC-MAX相互作用的亲和力相对弱(Kd=176nM)。然而,使用稳定的MYC-MAX复合物与现有技术先导物5a(US2016/0264560)测量了对DNA的结合亲和力,获得了阳性结果。使用表面等离子体共振(surface plasmon resonance,SPR),我们建立了稳定的MYC-MAX二聚体对芯片表面上经固定E-BOX寡核苷酸的特征性结合响应。当与载剂对照相比时,在流过芯片表面之前将二聚体与处理化合物一起孵育在传感图(sensogram)中显示出扰动。将化合物与10μM的二聚体一起孵育,并测量其防止与DNA相互作用的能力(图1-B栏)。还发现了被观察到与MYC没有相互作用的化合物在防止二聚体与DNA结合方面没有作用,并且观察到在DNA与单独的化合物之间没有相互作用。
表1:活性总结
a–在具有<0.1%DMSO的MES(pH 6.0)中通过DLS测量的。b–相对于5a Req。c–在用ATG-MYC转染的CEF中测量的。d–抑制所有细胞生长。NT–未测试。
通过检查ATG-MYC表达载体在CEF中建立微肿瘤的能力的病灶测定进行了对抗MYC活性的最终评估(Bos et al.,Genes&Development 1990,4(10),1677–1687.)。在该测定中检查了来自结合研究的活性化合物对微肿瘤形成的抑制(图1-C栏)。发现数种新化合物以与5a相似的效力抑制微肿瘤形成(表1)。
在乙醇中在存在过量甲醇钠的情况下,将α,β-不饱和酮2i与呋喃甲酰亚胺(furancarboximidine)8回流以产生羧酸9,通过形成酰氯并将其与NH4OH反应的策略将羧酸9转化为相应的酰胺,以得到嘧啶10(方案2)。10a具有与5a相当的活性谱。
方案2.嘧啶合成。
总的来说,5g是理想的,因为其易于获取,具有大大提高的溶解度,缺少不稳定的硝基,并且显示出与5a相似的结合和效力。通过Bio-FET使用浓度曲线,5g亲和力为12.5±4.1nM。在小鼠中进行10mg/kg i.v.PK研究,以确定这些有利的特性是否转化为改进的PK。小鼠PK的非房室分析随后对大鼠进行的异速生长尺度律(allometric scaling),提供了与先前针对5a进行的大鼠PK研究的比较,并且将其示于表2中。这种相对简单的取代已将平均停留时间从1小时显著提高至4.8,产生了对暴露的30倍提高(AUC)。这表明在通过5a发现的化学空间中有足够的可塑性,以在不损害效力的情况下改进其物理化学特性。
表2.5a(现有技术)与5g(本文中改进)的PK比较。
a–值是在大鼠中确定的那些的异速生长尺度律。b–在C57Bl6小鼠中确定的值。
本公开内容提供了保留现有技术5a的效力但具有提高的体内稳定性和溶解度的新的化合物系列。这是出人意料的“金发女孩效应改进(goldilocks effectimprovement)”,其中由支架缀合所赋予的疏水性对于与MYC的结合本质上是必需的,但是这种疏水性不利地影响了这样的分子的药动学特性。因此,为了溶解性而进行了对5g的略微活性损害,提供了更具类药性(drug-like)的先导化合物以用于靶向MYC。
治疗性应用
本文中所述的c-Myc抑制剂化合物可用于多种治疗性或预防性(例如抗肿瘤)应用,例如,压制或抑制c-Myc介导的细胞活性,以及治疗癌症或预防肿瘤的发生(特别是MYC依赖性肿瘤)。在一些实施方案中,治疗性应用涉及在对象中预防肿瘤的发生或治疗癌症。通常来说,治疗性方法需要向对象施用包含有效量的本文中所述的c-Myc抑制剂的药物组合物。
适合于用该组合物和方法治疗的癌症和肿瘤可以是存在于多种组织和器官中的那些。它们还包括在这些组织和/或器官的组成细胞中发现的癌细胞、肿瘤细胞,包括恶性肿瘤细胞等。一些实例包括脑肿瘤(多形性胶质母细胞瘤等)、脊髓肿瘤、上颌窦癌、胰腺癌、牙龈癌、舌癌、唇癌、鼻咽癌、中咽癌(mesopharyngeal cancer)、下咽癌、喉癌、甲状腺癌、甲状旁腺癌、肺癌、胸膜肿瘤、癌性腹膜炎、癌性胸膜炎、食管癌、胃癌、结肠癌、胆管癌、胆囊癌、胰腺癌、肝癌、肾癌、膀胱癌、前列腺癌、阴茎癌、睾丸肿瘤、肾上腺癌、宫颈癌、子宫内膜癌、阴道癌、外阴癌、卵巢癌、纤毛上皮癌、恶性骨肿瘤、软组织肉瘤、乳腺癌、皮肤癌、恶性黑素瘤、基底细胞瘤、白血病、骨髓纤维化伴髓样化生、恶性淋巴瘤肿瘤、霍奇金病(Hodgkin’sdisease)、浆细胞瘤和胶质瘤。
通常来说,治疗应影响对象、组织或细胞以获得所期望的药理学和/或生理学作用。就完全或部分预防疾病或其体征或症状而言,该作用可以是预防性的。就部分或完全治愈与异常c-Myc表达或生物化学活性相关或者由其介导的疾病或病症(例如,肿瘤生长)或者改善可归因于该病症的不良作用而言,该作用也可以是治疗性的。合适的对象包括无脊椎动物、脊椎动物、哺乳动物,特别是人。所描述的c-Myc抑制剂化合物可单独或与多种药物中的任一种联合使用,所述药物包括已知的抗肿瘤药物(antitumor drug)(抗肿瘤药物(antineoplastic drug))、肿瘤转移抑制剂、血栓形成抑制剂、关节破坏的治疗性药物、镇痛药、抗炎药、免疫调节剂(immunoregulator)(或免疫调制剂(immunomodulator))和/或免疫抑制剂,其可不受限于特定的物种使用,只要它们有效或有利地发挥作用即可。
所述化合物可单独施用于需要治疗的对象。更优选地,它们以与多种药理学上可接受的添加剂中的任一种混合的药物组合物或制剂的形式施用。例如,所述化合物可以以适合于经口、表面、肠胃外施加等的方便的药物组合物或制剂的形式施用。本发明的药物组合物可根据本领域公知的和常规实践的方法制备。参见,例如,Remington:The Scienceand Practice of Pharmacy,Mack Publishing Co.,20th ed.,2000;和Sustained andControlled Release Drug Delivery Systems,J.R.Robinson,ed.,Marcel Dekker,Inc.,New York,1978。药物组合物优选在GMP条件下制造。用于肠胃外施用的制剂可例如包含赋形剂、无菌水或盐水、聚亚烷基二醇(例如聚乙二醇)、植物来源的油或氢化萘。生物相容性的、可生物降解的丙交酯聚合物、丙交酯/乙交酯共聚物或聚氧乙烯-聚氧丙烯共聚物可用于控制化合物的释放。用于所公开化合物的另一些潜在可用的肠胃外递送系统包括乙烯-乙酸乙烯酯共聚物颗粒、渗透泵、可植入的输注系统以及脂质体。用于吸入的制剂可包含赋形剂(例如乳糖),或者可以是包含例如聚氧乙烯-9-月桂基醚、甘氨胆酸盐和脱氧胆酸盐的水溶液剂,或者可以是用于以滴鼻剂形式或作为凝胶施用的油性溶液剂。
包含c-Myc抑制性化合物的药物组合物可以以治疗有效量或剂量局部或全身施用。它们可肠胃外、肠内、通过注射、快速输注、鼻咽吸收、皮肤吸收、直肠和经口来施用。应用的c-Myc抑制剂以足以在有此需要的对象中实现所期望的治疗作用(例如,消除或改善与肿瘤发生和生长相关的症状)的量施用于对象。可改变药物组合物中活性成分的实际剂量水平,以便获得有效实现所期望的治疗响应而对对象无毒的活性成分的量。
选择的剂量水平取决于多种药动学因素,包括所使用特定组合物的活性、施用途径、施用时间和所使用特定化合物的排泄速率。其还取决于治疗持续时间,与所使用的特定组合物组合使用的其他药物、化合物和/或物质,所治疗对象的年龄、性别、体重、状况、一般健康和既往病史,以及类似因素。用于确定最佳剂量的方法在本领域中有描述,例如,Remington:The Science and Practice of Pharmacy,Mack Publishing Co.,20th ed.,2000。对于给定的c-Myc抑制剂化合物,本领域技术人员可通过使用常规实践的制药方法来确定抑制c-Myc的药剂的有效量。体外或原位研究中使用的剂量可在可用于体内施用药物组合物的量方面提供可用指导,并且动物模型可用于确定用于治疗特定病症的有效剂量。通常来说,药学有效剂量将为约0.001至100mg/kg待治疗对象体重。
本文中所述的c-Myc抑制剂化合物和其他治疗方案通常在多个场合下施用于对象。单剂量之间的间隔可以是每天、每周、每月或每年。间隔也可以是无规律的,如通过测量用于对象中的c-Myc抑制剂化合物和其他治疗剂的血液水平所指示的。在一些方法中,将剂量调节至达到血浆化合物浓度为1至1000μg/ml,并且在一些方法中,为25至300μg/ml或10至100μg/ml。或者,治疗剂可作为缓释制剂施用,在这种情况下,需要较低频率的施用。剂量和频率取决于c-Myc抑制剂化合物和其他药物在对象中的半衰期而变化。施用的剂量和频率可取决于治疗是预防性还是治疗性的而变化。在预防性应用中,在很长一段时间内以相对不频繁的间隔施用相对低的剂量。一些对象可能会在其余生中继续接受治疗。在治疗性应用中,有时需要以相对短的间隔使用相对高的剂量直至疾病的进展降低或终止,并且优选地直至对象显示出疾病症状的部分或完全改善。此后,对象可施用以预防性方案。
实施例
除非另外说明,否则所有溶剂和化学物质均获取自Thermo-Fisher或MilliporeSigma。除非另外说明,否则溶剂是无水的。化合物的纯化通过在1mm PLC硅胶60F254板上进行的制备型TLC以及通过在Teledyne ISCO Combiflash Rf+Lumen上进行的快速色谱来进行。化合物和中间体通过在指示溶剂中于Bruker DPX-400或NEO-500仪器上进行的NMR以及在Agilent ESI-TOF上进行的高分辨质谱来表征。>95%的纯度通过在Agilent 1260Infinity上进行的HPLC分析来确定(见补充)。通过2个数据库检索(ZINC Patterns、FAF-Drugs4)筛选化合物中已知的PAINS化合物。
合成方法:
HPLC分析。所有生物受试化合物均在Agilent 1260 Infinity仪器上进行纯化。溶剂A为H2O+0.1%TFA,溶剂B为MeCN+0.1%TFA。方法如下:在VYDAC C18柱(5μm,10mm×250mm)上使用10mL/分钟的流量,在45分钟内梯度为1→95%,收集级分持续70分钟时间。通过在250、254、210和280nm处的UV吸收来检测化合物。通常来说,化合物在约55分钟时洗脱。所有化合物被评估为具有95%的更高纯度。
LC-MS分析。所有生物受试化合物均在采用Agilent InfinityLab LC/MSD的Agilent 1260 Infinity 2仪器上进行纯化。溶剂A为H2O+0.1%TFA,溶剂B为MeCN+0.1%TFA(Honeywell)。方法如下:在ZORBAX 300SB-C8(5μm,4.6×50mm)柱上使用0.5mL/分钟的流量,在6.5分钟内梯度为10→95%,总运行时间为10分钟。通过在210、254、230和280nm处的UV吸收来检测化合物。
快速色谱。化合物和中间体在Teledyne ISCO Combiflash Rf+Lumen仪器上使用RediSep 12g二氧化硅柱使用DCM和甲醇来纯化。将柱用100.8mL溶剂平衡。在25分钟内以0→25%MeOH运行柱。
1a:在室温下将4’-氰基-2-溴苯乙酮(10g,45mmol)溶解于THF(150mL)中。然后,添加吡啶(7mL,90mmol),并将所得混浊溶液搅拌过夜。将形成的黄色沉淀过滤,用醚洗涤并在真空下干燥,得到13g吡啶.盐1a。
方案3:
(a)TosMIC,K2CO3,MeOH;(b)4-碘苯乙酮,Pd(OAc)2,Cul,DMF,140C;(c)TMSBr,NEt3,NBS,DCM;(d)Py,THF
1b:将4-乙酰基苯甲醛(500mg,3.4mmol)和对甲苯磺酰基甲基异氰酸酯(800mg,3.4mmol)溶解于无水甲醇(50mL)中。然后,添加K2CO3(560mg,3.4mmol),并将混合物在室温下搅拌过夜。将反应物用乙酸乙酯和水萃取,并在减压下除去溶剂,得到11(630mg,3.4mmol)。
1HNMR(400MHz,CDCl3):δ=8.01(d,J=8Hz,2H),7.96(s,1H),7.75(d,J=8Hz,2H),7.50(s,1H),2.63(s,3H).
将唑11固体溶解于无水DCM(100mL)中,并添加溴代三甲基硅烷(0.9ml,6.8mmol),随后添加三乙胺(1.4mL,10mmol)。将反应物在室温下搅拌过夜。将反应物用水和盐水洗涤,并使有机相在减压下蒸发。将所得深棕色油状物再溶解于无水THF(100mL)中,并添加N-溴代琥珀酰亚胺(605mg,3.4mmol)。将反应物在室温下搅拌30分钟,然后用乙酸乙酯和水萃取。将所得棕色油状物溶解于DCM中,并通过硅胶垫过滤,并蒸发至干,得到为黄色油状物的12(440mg,1.65mmol)。
1HNMR(400MHz,CDCl3):δ=8.04(d,J=8Hz,2H),7.98(s,1H),7.76(d,J=8Hz,2H),7.52(s,1H),4.43(s,2H).
1c:将噻唑(2.3mL,32.52mmol)、4-碘苯乙酮(4g,16.26mmol)、碘化铜(I)(6.2g,32.52mmol)和乙酸钯(II)(183mg,0.813mmol)溶解于密封管中的无水DMF(10mL)中。将反应混合物在150℃下加热48小时。然后,将溶剂反应混合物蒸发至干并吸附在硅胶上。将产物通过硅胶柱色谱,使用Hex/AcOEt(7∶3)作为洗脱液进行纯化,得到为黄色固体的13(2g,9.85mmol)。
1HNMR(500MHz,CDCl3):δ=8.07(d,J=8Hz,2H),8.03(d,J=8Hz,2H),7.94(d,J=3Hz,1H),7.43(d,J=3Hz,1H),2.64(s,3H).
将固体13(1g,5mmol)溶解于无水DCM(50mL)中,并添加溴代三甲基硅烷(1.3ml,10mmol),随后添加三乙胺(2mL,15mmol)。将反应物在室温下搅拌过夜。将反应物用水和盐水洗涤,并使有机相在减压下蒸发。将所得深棕色油状物再溶解于无水THF(50mL)中,并添加N-溴代琥珀酰亚胺(890mg,5mmol)。将反应物在室温下搅拌30分钟,然后用乙酸乙酯和水萃取。将所得棕色油状物溶解于二氯甲烷中,并通过硅胶垫过滤,并蒸发至干,得到为黄色油状物的14(1.25g,4.4mmol)。
1HNMR(600MHz,CDCl3):δ=8.17-8.05(m,4H),7.98(d,J=3Hz,1H),7.47(d,J=3Hz,1H),4.50(s,2H).
将溴代衍生物14(1.25g,4.44mmol)溶解于THF(15mL)中,并添加吡啶(0.85mL,9mmol)。将所得混浊溶液搅拌过夜。将形成的黄色沉淀过滤,用醚洗涤并在真空下干燥,得到1.8g的吡啶盐1c。
化合物2a至2h的合成
2a:将2-乙酰基呋喃(1.5g,13.64mmol)和LiOH(327mg,13.64mmol)在MeOH(100mL)中搅拌,然后添加4-甲酰基苯甲酸甲酯(2.2g,13.64mmol)。在30分钟之后,形成厚的无色沉淀。将沉淀过滤并在真空下干燥,得到为无色固体的2a(70%)。
2b:将2-乙酰基噻唑(2g,15.72mmol)和LiOH(376mg,15.72mmol)在MeOH(100mL)中搅拌,然后添加4-甲酰基苯甲酸甲酯(2.6g,15.72mmol)。在30分钟之后,形成厚的淡黄色沉淀。将沉淀过滤并在真空下干燥,得到为淡黄色固体的2b(73%)。
2c:将1-甲基-2-乙酰基咪唑(1.8g,16.36mmol)和LiOH(392mg,16.36mmol)在MeOH(100mL)中搅拌,然后添加4-甲酰基苯甲酸甲酯(2.6g,16.36mmol)。在30分钟之后,形成厚的黄色沉淀。将沉淀过滤并在真空下干燥,得到为黄色固体的2c(63%)。
2d:将1-(1-甲基-1H-1,2,3-三唑-5-基)乙酮(1.9g,15.20mmol)和LiOH(364mg,15.20mmol)在MeOH(100mL)中搅拌,然后添加4-甲酰基苯甲酸甲酯(2.5g,15.20mmol)。在30分钟之后,形成厚的带褐色的沉淀。将沉淀过滤并在真空下干燥,得到为浅橙色固体的2d(35%)。
2e:在氮气氛、-78℃下,向唑(0.1mL,1.79mmol)在THF(10mL)中的溶液添加1.1当量的n-BuLi(己烷中的2.5M)(0.85mL,2.14mmol)。将所得溶液在-78℃下搅拌20分钟,并添加2当量的ZnCl2(醚中的1.0M溶液)(4mL,3.57mmol)。将该混合物温热至0℃并搅拌1小时,并添加1当量的CuI(340mg,1.79mmol)。在10分钟之后,添加2当量的苯甲酸,4-(3-氯-3-氧代-1-丙烯-1-基)-甲酯(800mg,3.57mmol)。将反应物保持在0℃下直至TLC显示出完全转化。将有机溶液用乙酸乙酯稀释,并依次用NH4OH/H2O(1∶1)、水和盐水洗涤。将产物通过硅胶色谱使用n-Hex/EtOAc(7∶3)进行纯化,获得为白色固体的2e(57%)。
1HNMR(600MHz,CDCl3):δ=8.11(d,J=12Hz,2H),8.05(d,J=12Hz,1H),7.92(s,1H),7.87(d,J=12Hz,1H),7.77(d,J=12Hz,1H),7.44(s,1H),3.96(s,3H);13CNMR(150MHz,DMSO-d6):δ=175.62,165.87,158.48,144.25,141.57,137.94,131.64,129.71,128.85,128.26,122.74,51.89.
2f:将2-乙酰基呋喃(2g,18.2mmol)和苯甲醛(1.85mL,18.2mmol)溶解于乙醇(50mL)中。向其添加10%NaOH的水溶液(50mL),并将反应物在室温下搅拌过夜。然后,将其用乙酸酸化并用乙酸乙酯萃取。将所得油状物通过柱色谱,使用n-Hex/EtOAc(8∶2至7∶3)作为洗脱液进行纯化,获得为白色固体的2f(69%)。
2g:将2-乙酰基呋喃(1g,9mmol)和LiOH(220mg,9mmol)在MeOH(50mL)中搅拌,然后添加2-噻唑甲醛(0.8mL,9mmol)。在30分钟之后,形成深棕色沉淀。将沉淀过滤并在真空下干燥,得到为棕色固体的2g(50%)。
2h:将2-乙酰基呋喃(316mg,2.9mmol)和LiOH(70mg,2.9mmol)在MeOH(10mL)中搅拌,然后添加4-(1H-四唑-5-基)苯甲醛(500mg,2.9mmol)。在30分钟之后,形成黄色沉淀。将沉淀过滤并在真空下干燥,得到为黄色固体的2h(71%)。
2i:将4-乙酰基苄腈(435mg,3mmol)和LiOH(72mg,3mmol)在MeOH(20mL)中搅拌,然后添加4-甲酰基苯甲酸甲酯(500mg,3mmol)。在30分钟之后,形成黄色沉淀。将沉淀过滤并在真空下干燥,得到为黄色固体的2i(56%)。
化合物5a至o的一般性操作。将查耳酮2(1g,4mmol.)和NH4OAc(9.2g,120mmol)溶解于乙酸(20mL)和DMF(30mL)的混合物中。向其添加吡啶盐1(1.2g,4mmol),并将反应混合物在100℃下加热过夜。使溶剂在真空下蒸发,并将其余棕色油状物溶解于DCM(100mL)中,并添加固体NaHCO3直至气体释放停止。将有机相经MgSO4干燥并在减压下蒸发。使用为棕色固体的Et2O-MeOH将产物3粉碎。该物质无需进一步纯化即可继续进行。向3在THF∶H2O(9∶1)中的溶液添加LiOH(2.5g,104mmol),并搅拌过夜。将反应混合物通过硅胶垫过滤,并蒸发至干,得到羧酸4。将4(3g,8.2mmol)溶解于无水DCM(100mL)以及草酰氯(0.7mL,8.2mmol)随后是1滴DMF。将反应物在室温下搅拌过夜,然后在真空中除去溶剂,并将其余固体再溶解于无水DCM(100mL)中。将该溶液倒在NH4OH溶液(50mL)上,并将反应混合物搅拌30分钟。将有机层分离、干燥并在真空下蒸发,得到棕色油状物,将其纯化以获得吡啶5。
5b:
1HNMR(600MHz,DMSO-d6):δ=8.54(d,J=12Hz,2H),8.35(s,1H),8.12(m,3H),8.08(d,J=6Hz,2H),8.04(d,J=12Hz,2H),7.94(s,1H),7.50(brs,1H),7.42(s,1H),6.75(s,1H);13CNMR(150MHz,DMSO-d6):δ=167.23,154.81,152.78,149.39,148.74,144.66,142.48,139.50,134.99,132.70,128.25,127.77,127.19,118.83,117.28,115.59,112.48,111.77,110.14;
HRMS(ESI-TOF):C24H17N3O2的m/z计算值:366.1237(M+H)+;实测值:366.1238。
5c:
1HNMR(600MHz,DMSO-d6):δ=8.54(m,3H),8.47(d,J=12Hz,1H),8.16(brs,1H),8.15(d,J=6Hz,2H),8.10-8.07(m,5H),8.00(d,J=6Hz,1H),7.51(brs,1H);13CNMR(150MHz,DMSO-d6):δ=167.98,167.20,155.01,151.43,149.35,144.47,141.78,139.12,135.21,132.87,128.35,127.75,127.27,123.37,119.94,118.76,116.21,112.08;
HRMS(ESI-TOF):C22H14N4uOS的m/z计算值:383.0961(M+H)+;实测值:383.0960。
5d:
1HNMR(600MHz,DMSO-d6):δ=8.58(s,1H),8.56(d,J=6Hz,2H),8.44(s,1H),8.41(s,1H),8.16(brs,1H),8.15(d,J=6Hz,2H),8.09(d,J=6Hz,2H),8.06(d,J=6Hz,2H),7.56(s,1H),7.51(s,1H);13CNMR(150MHz,DMSO-d6):δ=167.19,159.87,155.32,149.11,146.41,142.04,141.50,138.94,135.23,132.80,128.99,128.35,127.90,127.28,120.01,119.00,118.75,112.03;
HRMS(ESI-TOF):C22H14N4O2的m/z计算值:367.1189(M+H)+;实测值:367.1183。
5e:
1HNMR(600MHz,DMSO-d6):δ=8.51(d,J=6Hz,2H),8.45(d,J=6Hz,1H),8.41(d,J=1.5Hz,1H),8.15(brs,1H),8.09(d,J=3Hz,4H),8.03(d,J=6Hz,2H),7.96(d,J=12Hz,2H),7.50(brs,1H),7.42(s,1H),7.11(d,J=1Hz,1H),4.23(s,3H);13CNMR(150MHz,DMSO-d6):δ=167.25,154.25,151.18,148.53,143.60,142.73,139.54,135.02,132.83,132.38,128.36,128.00,127.09,125.79,119.09,118.81117.64,111.75,36.47;
HRMS(ESI-TOF):C23H17N5O的m/z计算值:380.1506(M+H)+;实测值:380.1504。
5f:
1HNMR(600MHz,DMSO-d6):δ=8.60(s,1H),8.53(d,J=6Hz,2H),8.50(s,1H),8.36(s,1H),8.20(d,J=6Hz,2H),8.16(brs,1H),8.09(d,J=12Hz,2H),8.05(d,J=12Hz,2H),7.53(brs,1H),4.50(s,3H);13CNMR(150MHz,DMSO-d6):δ=167.18,155.05,149.18,147.61,142.36,139.00,135.62,135.17,134.48,132.85,128.20,127.91,127.39,120.20,119.50,118.75,118.45,112.0,37.96;
HRMS(ESI-TOF):C22H16N6O的m/z计算值:381.1458(M+H)+;实测值:381.1457。
5g:
1HNMR(600MHz,DMSO-d6):δ=8.46(d,J=12Hz,2H),8.28(s,1H),8.16(brs,1H),8.12(m,3H),8.08(d,J=12Hz,2H),8.00(d,J=3Hz,1H),7.94(s,1H),7.86(s,d,J=3Hz,1H),7.51(brs,1H),7.40(s,1H),6.75(s,1H);13CNMR(150MHz,DMSO-d6):δ=167.29,166.58,155.80,153.00,149.26,148.55,144.50,144.08,139.78,139.67,134.90,133.78,128.77,127.77,127.13,126.48,120.88,116.62,114.92,112.43,109.89;
HRMS(ESI-TOF):C25H17N3O2S的m/z计算值:424.1114(M+H)+;实测值:424.1116。
5h:
1HNMR(600MHz,DMSO-d6):δ=8.52(s,1H),8.45(d,J=12Hz,2H),8.27(s,1H),8.15(brs,1H),8.12(m,3H),8.04(s,1H),7.93(m,3H),7.94(s,1H),7.84(s,1H),7.50(brs,1H),7.39(s,1H),6.74(s,1H);13CNMR(150MHz,DMSO-d6):δ=167.28,155.89,153.03,152.14,150.21,149.21,148.51,144.48,139.81,138.18,134.88,128.25,128.17,127.68,127.13,124.35,122.81,116.45,114.76,112.42,109.84;
HRMS(ESI-TOF):C25H17N3O3的m/z计算值:408.1343(M+H)+;实测值:408.1350。
5i:
1HNMR(600MHz,CDCl3):δ=8.28(d,J=12Hz,2H),7.96(s,1H),7.85(s,1H),7.82(d,J=12Hz,2H),7.78(d,J=6Hz,2H),7.61(s,1H),7.58-7.52(m,3H),7.27(s,1H),6.62(s,1H);13CNMR(150MHz,CDCl3):δ=154.94,153.20,150.02,149.62,143.12,142.98,137.76,132.07,128.92,128.75,127.18,126.63,118.43,116.77,115.67,112.07,111.76,109.01;
HRMS(ESI-TOF):C22H14N2O的m/z计算值:323.1179(M+H)+;实测值:323.1182。
5j:
1HNMR(600MHz,DMSO-d6):δ=8.37(d,J=12Hz,2H),8.31(s,1H),8.15(s,1H),8.12(s,1H),8.11(d,J=12Hz,2H),8.05(d,J=6Hz,1H),8.00(d,J=6Hz,1H),7.94(s,1H),7.86(s,1H),7.37(s,1H),6.74(s,1H);13CNMR(150MHz,DMSO-d6):δ=166.48,164.37,156.18,152.55,149.47,144.83,144.51,144.09,141.89,139.04,133.99,127.67,126.58,123.05,120.95,114.96,113.28,112.53,110.20;
HRMS(ESI-TOF):C21H13N3OS2的m/z计算值:388.0573(M+H)+;实测值:388.0574。
5k:
1HNMR(600MHz,DMSO-d6):δ=8.54(d,J=12Hz,2H),8.34(s,1H),8.18(d,J=12Hz,2H),8.11(s,1H),8.07(d,J=12Hz,2H),8.03(d,J=12Hz,3H),7.94(s,1H),7.41(s,1H),6.74(s,1H);13CNMR(150MHz,DMSO-d6):δ=160.11,154.69,152.94,149.45,149.31,144.53,142.68,135.00,134.00,132.68,127.74,127.26,126.28,118.86,116.79,115.05,112.42,111.64,109.90;
HRMS(ESI-TOF):C23H14N6O的m/z计算值:391.1302(M+H)+;实测值:391.1315。
用于合成化合物5m至5o的方案
将羧酸4a(1g,2.7mmol)溶解于无水DCM(100mL)中,并添加草酰氯(0.5mL,5mmol)随后是DMF(1滴)。将反应物在室温下搅拌过夜。然后,在真空中除去溶剂,并将其余固体再溶解于无水DCM(100mL)中。将该溶液倒在(a)甲胺和DIPEA(1∶1)(25mL);(b)甲烷磺酰胺(300mg,3.15mmol)和DIPEA(10mL)或(c)肼和DIPEA(1∶1)(25mL)的溶液上,并将反应混合物搅拌30分钟。然后,将有机层用水洗涤,分离,干燥并在真空下蒸发,分别得到5l、5m和5n。将产物通过制备型TLC,使用DCM/MeOH(85∶15)作为洗脱液进行纯化。
5l:
1HNMR(600MHz,DMSO-d6):d=8.63(m,2H),8.53(d,J=12Hz,2H),8.35(s,1H),8.14(d,J=12Hz,2H),8.11(s,1H),8.04(m,3H),7.94(s,1H),7.42(s,1H),6.74(s,1H),2.84(s,3H);13CNMR(150MHz,DMSO-d6):d=165.92,154.82,152.78,149.39,148.70,144.66,142.48,139.29,135.19,132.70,127.83,127.77,127.24,118.83,117.25,115.55,112.48,111.77,110.13;
HRMS(ESI-TOF):C24H17N3O2的m/z计算值:380.1393(M+H)+;实测值:380.1394。
5m:
1HNMR(600MHz,DMSO-d6):d=8.54(d,J=6Hz,2H),8.32(s,1H),8.12(d,J=6Hz,2H),8.08(s,1H),8.01(m,4H),7.94(brs,1H),7.93(s,1H),7.40(s,1H),6.74(m,1H),2.89(s,3H);13CNMR(150MHz,DMSO-d6):d=169.75,154.73,152.86,149.32,144.57,142.58,140.75,137.93,132.68,129.74,129.00,127.76,126.34,118.85,117.10,115.40,112.43,111.68,109.98,43.13;
HRMS(ESI-TOF):C24H17N3O4S的m/z计算值:444.1012(M+H)+;实测值:444.1017。
5n:
1HNMR(600MHz,DMSO-d6):d=9.96(s,1H),8.54(d,J=12Hz,2H),8.35(s,1H),8.14(d,J=6Hz,2H),8.11(s,1H),8.03(d,J=12Hz,3H),7.94(s,1H),7.41(s,1H),6.75(s,1H),4.57(s,2H);13CNMR(150MHz,DMSO-d6):d=165.11,154.81,152.77,149.39,148.69,144.66,142.48,139.34,134.01,132.70,127.76,127.27,118.82,117.24,115.55,112.47,111.77,110.13;
HRMS(ESI-TOF):C23H16N4O2的m/z计算值:381.1346(M+H)+;实测值:381.1358。
7a的合成
向4-溴-2-(4-氰基苯基)吡啶(200mg,0.77mmol.)在无水DME(3mL)中的溶液添加4-氨基羰基苯基硼酸(152mg,0.80mmol)和水(1mL)。然后,添加K2CO3(320mg,2.3mmol.)和Pd(PPh3)4(36mg,0.03mmol.),并将反应物在85℃下加热过夜。使反应混合物蒸发,吸附在硅胶上,并通过柱色谱,使用EtOAc作为洗脱液进行纯化,得到为白色固体的7a(160mg)。
1HNMR(600MHz,DMSO-d6):d=8.82(d,J=6Hz,1H),8.45(m,3H),8.13(brs,1H),8.06(m,4H),7.84(d,J=6Hz,1H),7.49(brs,1H);13CNMR(150MHz,DMSO-d6):d=167.25,154.98,150.54,147.61,142.84,139.54,134.89,132.69,128.25,127.66,127.09,121.28,118.83,111.60;
HRMS(ESI-TOF):C19H13N3O的m/z计算值:300.1131(M+H)+;实测值:300.1132。
7b的合成
向2-溴-6-(呋喃-2-基)吡啶(280mg,1.25mmol)在无水DME(3mL)中的溶液添加4-氰基苯基硼酸(220mg,1.3mmol.)和水(1mL)。然后,添加K2CO3(520mg,3.75mmol.)和Pd(PPh3)4(60mg,0.05mmol.),并将反应物在85℃下加热过夜。使反应混合物蒸发,吸附在硅胶上,并通过柱色谱,使用Hex/EtOAc(8∶2)作为洗脱液进行纯化,得到为白色固体的7b(180mg)。
1HNMR(600MHz,CDCl3):d=8.23(d,J=6Hz,2H),7.86(t,J=6Hz,1H),7.80(m,1H),7.73(d,J=6Hz,1H),7.66(d,J=6Hz,1H),7.59(s,1H),7.22(s,1H),6.60(m,1H);13CNMR(150MHz,CDCl3):d=154.24,153.10,149.15,143.11,142.84,137.26,132.05,127.04,118.42,117.52,111.69,108.78;
HRMS(ESI-TOF):C16H10N2O的m/z计算值:247.0866(M+H)+;实测值:247.0866。
化合物10a至c的一般性操作。向呋喃甲酰亚胺8(250mg,1.72mmol)在IPA(20mL)中的溶液添加Na(45mg,2mmol),并将反应回流2小时。之后,添加2(500mg,1.72mmol),并将混合物回流过夜。然后,将其在真空下蒸发至干,溶解于DCM∶MeOH(8∶2)中,并通过硅胶垫过滤。将滤液蒸发至干,得到红色油状物。使用EtOAc∶Hex(1∶1)使羧酸9沉淀为黄色固体(55%)。该物质无需进一步纯化即可继续进行。将9(200mg,0.55mmol)溶解于DCM(20mL)以及草酰氯(0.2mL,36mmol)随后是1滴DMF。将反应物在室温下搅拌过夜。在真空中除去溶剂,并将其余固体再溶解于DCM(50mL)中。将该溶液倒在NH4OH溶液(50mL)上,并将反应混合物搅拌30分钟。将有机层分离、干燥并在真空下蒸发,得到棕色油状物,将其纯化以获得嘧啶10。
10a:
1HNMR(600MHz,DMSO-d6):d=8.66(s,1H),8.65(d,J=2Hz,2H),8.55(d,J=12Hz,2H),8.18(s,1H),8.10(m,4H),8.03(s,1H),7.60(s,1H),7.55(s,1H),6.79(s,1H);13CNMR(150MHz,DMSO-d6):d=167.24,163.91,162.60,157.33,151.72,146.12,140.41,138.39,136.65,132.89,128.20,128.04,127.35,118.55,114.35,113.49,112.61,111.30;
HRMS(ESI-TOF):C22H14N4O2的m/z计算值:367.1189(M+H)+;实测值:367.1202。
10b:
1HNMR(400MHz,DMSO-d6):d=8.35(d,2H),8.22(m,1H),8.10(d,2H),7.82(bs,2H),7.90(m,4H),7.80(d,2H),7.50(m,3H);
HRMS(ESI-TOF):C22H16N4O的m/z计算值:377.1402(M+H)+;实测值:377.1482。
10c:
1HNMR(400MHz,DMSO-d6):d=8.66(s,1H),8.65(d,J=2Hz,2H),8.55(d,J=12Hz,2H),8.18(s,1H),8.10(m,4H),8.03(s,1H),7.60(s,1H),7.55(s,1H),6.79(s,1H);
HRMS(ESI-TOF):C22H16N4O的m/z计算值:382.1555(M+H)+;实测值:382.1482。
生物学方法:
蛋白质表达和纯化。将经His标记的MYC、mMAX、MYC-MAX和MAX-MAX构建体在BL21大肠杆菌(E.coli)细胞中表达并如前所述进行纯化10。
FET功能化和再生。FET实验在环境温度下在Agile R100(NanomedicalDiagnostics)上进行。使用Ni-NTA根据制造商方案对芯片进行功能化。然后通过在50mMMES(pH 6.0)中与约100nM蛋白质一起孵育15分钟,使表面结合的Ni-NTA位点与经His标记的蛋白质结合。通过用250mM咪唑处理30分钟,随后在MES中全面洗涤,然后再引入经His标记的蛋白质,可使Ni-NTA功能化的芯片再生。
相对结合研究。将受试化合物在具有3%DMSO的MES(pH 6.0)缓冲液中溶解至所期望浓度。使蛋白质结合的芯片初始化,并将其在具有3%DMSO的MES缓冲液中清洗。对于相对结合研究,在单次运行中对10μM的6至8种受试化合物(包括5a)进行分析,并且确定Req并将其与5a的Req进行比较。在不同芯片上对化合物测试至少3次。
MYC亲和力评估。5g的亲和力通过找到浓度曲线的1/2Rmax来确定。允许5g的多种浓度与MYC平衡,并相对于浓度绘制Req值。拟合该数据的对数线通过Microsoft Excel来确定,并根据该线的方程计算出1/2Rmax的5g浓度。在3个芯片上重复该过程,并在那三个运行之间对亲和力求平均。
表面等离子体共振。所有实验均使用配备有研究级SA传感器芯片(BR1000032,GEHealthcare)的Biacore 3000仪器(GE Healthcare)进行。将经生物素标记的EBOX DNA(生物素-GTAGGCCACGTGACCGGG,Eurofins Operon)与10μM未经标记的互补链混合并在95℃下加热5分钟,并随后缓慢冷却至室温持续20分钟以进行退火。将退火的EBOX dsDNA在运行缓冲液(1∶10HBS+EP,BR-1006-69,GE Healthcare)中稀释100倍,并将其注射在SA芯片上以进行捕获。在结合测定中,空白的SA芯片流通池用作参考流通池。在具有1%DMSO的运行缓冲液中,将化合物以10μM添加至MYC-MAX二聚体。将蛋白质和化合物在室温下孵育15分钟。将样品以30μL/分钟注射5分钟。在2.5分钟内监测与EBOX的结合。将芯片在10mM甘氨酸HCl(pH2.2)中再生.5分钟。
CEF测定。如前所述进行CEF细胞的ATG-MYC转染10。从1000×DMSO储液中添加化合物至培养基中的最终DMSO浓度<.1%。
呋喃分析。使用<1.0%DMSO,将化合物5a、5g和7a添加至PBS中的0.5mg/mL大鼠肝微粒体(合并的,Sigma-Aldrich)至终浓度为5μM。将化合物在37℃下孵育。在指定时间点移出10μL等分试样,并将其以1∶1000在包含1μM TAP的乙腈中稀释。在配备有Agilent ZORBAXSB-C8柱的Agilent 6100 Quadruple LC-MS系统上分析样品。使用H2O+0.1%甲酸和MeCN+0.1%甲酸作为流动相运行样品。在7分钟的运行(500μL/mL)中,H2O+0.1%甲酸的百分比自10至95%线性提高,并且MeCN+0.1%甲酸的百分比自90至5%线性降低。使用MassHunter软件(Agilent)进行母体化合物质量的离子提取和整合。使用Microsoft Excel进行运行的归一化和求平均。分析结果示于图2中。
溶解度分析。通过在DynaPro NanoStar检测器(Wyatt Technology)上进行动态光散射来分析化合物的溶解度。将化合物从1000×DMSO储液中以不同浓度溶解于MES(pH6.0)中。分析样品的聚集,并将未观察到聚集的最大浓度用作溶解度的量度。
PK分析。5g的药动学分析由Explora Biolabs进行。将12只C57BL/6(6只雄性,6只雌性)小鼠通过IV注射以10mg/kg施用5g。在注射之后2分钟以及0.08、0.25、0.5、1、2、8和24小时收集血液样品。通过Shimadzu VP系列10系统LC进行处理,随后在AppliedBiosystems/MDS SCIEX API 3000三重四极质谱仪上进行质量分析,通过整合分析解决方案(Integrated Analytical Solutions)进行生物分析。涉及动物的护理和使用的所有程序均由Explora BioLabs的IACUC批准。
Claims (9)
2.权利要求1所述的化合物,其中R1是噻唑基。
4.权利要求3所述的药物组合物,其中R1是噻唑基。
6.权利要求4所述的方法,其中R1是噻唑基。
7.抑制MYC-MAX二聚化的方法,其包括使MYC与有效量或浓度的权利要求1所述的化合物接触。
8.抑制MYC实现的转录激活的方法,其包括使MYC与有效量或浓度的权利要求1所述的化合物接触。
9.抑制MYC诱导的细胞增殖的方法,其包括使MYC与有效量或浓度的权利要求1所述的化合物接触。
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