CN103848795B - 一种1,2,5-噁二唑-2-氧化物组蛋白去乙酰化酶抑制剂及其制备方法和应用 - Google Patents
一种1,2,5-噁二唑-2-氧化物组蛋白去乙酰化酶抑制剂及其制备方法和应用 Download PDFInfo
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- CN103848795B CN103848795B CN201410083075.0A CN201410083075A CN103848795B CN 103848795 B CN103848795 B CN 103848795B CN 201410083075 A CN201410083075 A CN 201410083075A CN 103848795 B CN103848795 B CN 103848795B
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- oxadiazole
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- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/08—1,2,5-Oxadiazoles; Hydrogenated 1,2,5-oxadiazoles
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明涉及一种l,2,5‑噁二唑‑2‑氧化物组蛋白去乙酰化酶抑制剂及其制备方法和应用。所述化合物具有式I的结构。本发明的化合物，用于制备预防或治疗与组蛋白去乙酰化酶活性异常表达相关的哺乳动物疾病的药物。本发明还涉及含有式I结构化合物的药物组合物。
Description
技术领域
本发明涉及一种1,2,5-噁二唑-2-氧化物组蛋白去乙酰化酶抑制剂及其制备方法和应用，属于化学技术领域。
背景技术
组蛋白乙酰化状态受组蛋白乙酰化转移酶(histone acetyltransferases，HATs)和组蛋白去乙酰化酶(histone deacetylases，HDACs)双重调节。组蛋白乙酰化是一个动态的可逆过程，乙酰化与去乙酰化的动态平衡影响染色质的结构和基因表达。HAT将乙酰辅酶A上的疏水乙酰基转移到组蛋白的N端赖氨酸残基，中和掉一个正电荷，使DNA与组蛋白之间相互作用减弱，即减弱核小体中碱性氨基酸与DNA的静电吸引力，降低相邻核小体之间的聚集，染色质呈转录后活性结构，增加转录因子的进入，DNA易于解聚、舒展，有利于转录因子与DNA模板相结合从而激活转录；而HDAC通过组蛋白N端的去乙酰化，使组蛋白带正电荷，从而与带负电荷的DNA紧密结合，染色质呈紧密卷曲的阻抑结构，从而抑制某些基因的转录表达。目前在人体中发现了HDACs家族共有18个成员，根据其结构，功能及分布的不同可分为四类。其中，I类(HDAC1,2,3和8),II类(IIa:HDAC 4,5,7和9；IIb：HDAC 6和10)，IV类(HDAC11)属于锌离子依赖性水解酶，而III类HDACs(SIR 1—7)是NAD+依赖性的。
近来，越来越多的非组蛋白被证实为HDACs的底物，如转录因子，细胞骨架蛋白，分子伴侣等。正是由于HDACs具有如此复杂的功能，它的表达和活性失调与许多疾病密切相关，包括癌症，神经变性疾病，病毒感染，炎症，白血病，疟疾和糖尿病等，其中癌症无疑是对人类生命健康威胁最严重的疾病。研究表明，HDACs，尤其是HDAC I和II与肿瘤发生发展密切相关，如：抑制肿瘤细胞分化和凋亡，促进肿瘤细胞增殖，迁移和血管生成，增强肿瘤细胞对化疗药物的抵抗力等。此外，HDAC抑制剂(HDAC inhibitors，HDACi)能有效抑制癌细胞增殖，促进细胞分化与凋亡。而且，HDACi具有抗瘤谱广，毒副作用低的优点，它们对实体瘤，白血病，淋巴瘤都具有很好的抑制活性。因此，针对HDACs为靶点设计抑制剂已成为抗肿瘤药物研究的热点。
一氧化氮(NO)作为生物体内重要的信使分子，参与血管调节、神经传递、炎症与免疫反应等过程，同时NO也可以通过多种途径抑制肿瘤的发生发展。虽然NO在肿瘤进展中的作用机制尚不明确，但体内持续低浓度的NO可促进细胞生长，抑制细胞凋亡，而高浓度的NO则可产生细胞毒性，诱导肿瘤细胞凋亡，阻止肿瘤细胞的扩散和转移，且与正常细胞相比，肿瘤细胞对NO更敏感。NO供体型抗肿瘤药JS-K已被NCI列入快速研发计划。作为NO供体的呋咱氮氧化物(式II)逐渐被人们重视，越来越多的研究者尝试利用呋咱氮氧化合物作为NO供体进行肿瘤药物的设计合成并取得一定的进展。
HDACi在炎症、神经传递、血管调节及心血管疾病方面也存在潜在的应用价值，这与NO的作用不谋而合，根据此研究结果，两者应该在治疗某些疾病的过程中起到协同作用。2011年Key，H.J发现在治疗心肌肥大症的时候，两者的确起到协同作用；此后，又有研究者发现两者在治疗伤口愈合的时候同样会起到协同作用。
发明内容
本发明针对现有技术的不足，提供一种同时具有抑制去乙酰化酶和释放一氧化氮双重作用的1,2,5-噁二唑-2-氧化物组蛋白去乙酰化酶抑制剂及其制备方法和用途。
本发明技术方案如下：
一、1,2,5-噁二唑-2-氧化物组蛋白去乙酰化酶抑制剂
1,2,5-噁二唑-2-氧化物组蛋白去乙酰化酶抑制剂，具有通式I所示的结构，以及其光学异构体，非对映异构体和消旋体混合物，其药学上可接受的盐，溶剂合物或前药；
其中，
X是氧，硫或氮；
R1是各种C1-8的饱和脂肪链，带有支链的饱和脂肪链，烯烃链，炔烃链，烷氧链，芳酰基，杂芳基，C1-8杂烷基，带有取代基的芳香基或带有取代基的杂芳基；
R2是异羟肟酸，羧基，甲氧羰基，酰胺基或酰肼基；
R3是砜基，亚砜基或碳原子。
本发明所用的术语和定义含义如下：
“芳香基”是指芳香族碳环基团。优选的芳环含有6-10个碳原子。
“杂芳基”是芳族杂环，可以是单环或双环基团。优选的杂芳基包括噻吩基，呋喃基，吡咯基，吡啶基，吡嗪基，噻唑基，嘧啶基，喹啉基，四氮唑基，本病噻唑基，苯并呋喃基或吲哚基等。
“杂烷基”是饱和或不饱和、含碳原子和至少一个杂原子的链，其中任意一个杂原子不相邻。杂烷基中含有2-15个原子(碳原子)，优选含有2-10个原子。杂烷基可以是直链或支链，取代或未取代的。
“环烷基”是取代或未取代的，饱和或不饱和的环状基团，其含有碳原子和/或一个或多个杂原子。该环可以是单环或稠环，桥环或螺环的环系。单环通常有3-9个原子，优选有4-7个原子，多环含有7-17个原子，优选含有7-13个原子。
“芳酰基”是指芳香族碳环末端连有羰基的基团，优选的芳环含有6-10个碳原子。
“药学上可接受的盐”是指式(I)化合物具有疗效且无毒的盐形式。其可有任意酸性基团(如羧基)形成阴离子盐，或由任意碱性基团(如氨基)形成阳离子盐。本领域已知许多这样的盐。在任何酸性基团(如羧基)上形成的阳离子盐，或是在任何碱性基团(如氨基)上形成的阴离子盐，这些盐有许多是本领域已知的，如阳离子盐包括碱金属(如钠和钾)和碱土金属(镁和钙)的盐以及有机盐(如铵盐)。还可通过使用相应的酸处理碱性形式的(I)方便的获得阴离子盐，这样的酸包括无机酸如硫酸，硝酸，磷酸等；或有机酸如乙酸，丙酸，羟基乙酸，2-羟基丙酸，2-氧代丙酸，草酸，丙二酸，琥珀酸，马来酸，富马酸，苹果酸，酒石酸，2-羟基-1，2，3-丙二酸，乙磺酸，苯甲磺酸，4-甲基苯磺酸，环己基亚磺酸，2-羟基苯甲酸，4-氨基-2-羟基苯甲酸等。此外，熟练技术人员可根据溶解度，稳定性，容易制剂等因素取某种盐而舍另一种盐。这些盐的测定和最优化在熟练技术人员的经验范围内。
“溶剂合物”是溶质(如金属蛋白酶抑制剂)和溶剂(如水)组合形成的配合物。参见J.Honig等，The Van Nostrand Chemist’s Dictionary,p.650(1593)。本发明采用的药学上可接受的溶剂包括不干扰金属蛋白酶抑制剂的生物活性的那些溶剂(例如水，乙醇，乙酸，N,N-二甲基甲酰胺，二甲基亚砜以及该领域技术人员所指的或容易确定的溶剂)。
本文所用的“光学异构体”，“对映体”，“非对映体”，“消旋体”等定义了本发明化合物或生理上的衍生物所有可能的立体异构体的形式。除非另有指示，本发明化合物的化学命名包括所有可能的立体化学形式的混合物，所属混合物包含基本结构分子的所有非对映体和对映体，以及基本纯净的本发明化合物的单个异构体形式，即其中含有低于10％，优选低于5％，特别是低于2％，最有选低于1％的其他异构体。本发明类肽化合物各种立体异构体形式均明显包含于本发明的范围内。
式I化合物还可以其他被保护的形式或衍生物的形式存在，这些形式对本领域技术人员而言是显而易见的，均应该包含于本发明的范围内。
如上所述的取代基自身还可被一个或多个取代基取代。这样的取代基包括在C.hansch和A.Leo，Substituent Constants for Correlation Analysis in Chemistry and Biology(1979)中列出的那些取代基。优选的取代基包括，例如烷基，烯基，烷氧基，羟基，氧基，硝基，氨基，氨基烷基(如氨甲基等)，氰基，卤素，羧基，羰基烷氧基(如羰基乙氧基等)，硫基，芳基，环烷基，杂芳基，杂环烷基(如哌啶基，吗啉基，吡咯基等)，亚氨基，羟烷基，芳基氧基，芳基烷基，及其结合。
优选的，上述通式I中，
X是氧；
R1是C1-8的饱和脂肪链，C1-8的不饱和脂肪链，C1-9的芳香链，C1-8的含有杂原子的脂肪链，C1-9的杂环；
R2是羧基，甲氧羰基，乙氧羰基，异羟肟酸；
R3是砜基。
进一步优选的，上述式I化合物是下列之一：
4-(3-羧基丙氧基)-3-(苯基磺酰基)-1,2,5-噁二唑-2-氧化物(4a)；
4-(4-羧基丁氧基)-3-(苯基磺酰基)-1,2,5-噁二唑-2-氧化物(4b)；
4-((5-羧基戊基)氧)-3-(苯基磺酰基)-1,2,5-噁二唑-2-氧化物(4c)；
4-(2-(羧基甲氧基)乙氧基)-3-(苯基磺酰基)-1,2,5-噁二唑-2-氧化物(4d)；
4-(2-羧基-2-甲基丙氧基)-3-(苯基磺酰基)-1,2,5-噁二唑-2-氧化物(4e)；
(E)-4-((3-carboxyallyl)氧基)-3-(苯基磺酰基)-1,2,5-噁二唑-2-氧化物(4f)；
4-(2-(2-(羧基甲氧基)乙氧基)乙氧基)-3-(苯基磺酰基)-1,2,5-噁二唑-2-氧化物(4g)；
4-(4-羧基苯氧基)-3-(苯基磺酰基)-1,2,5-噁二唑-2-氧化物(4h)；
4-(3-羧基苯氧基)-3-(苯基磺酰基)-1,2,5-噁二唑-2-氧化物(7)；
4-(4-(羧甲基)苯氧基)-3-(苯基磺酰基)-1,2,5-噁二唑-2-氧化物(4j)；
(E)-4-(4-(2-羧甲基)苯氧基)-3-(苯基磺酰基)-1,2,5-噁二唑-2-氧化物(4k)；
4-(4-羧基-2-甲氧基苯氧基)-3-(苯基磺酰基)-1,2,5-噁二唑-2-氧化物(4l)；
4-((2-羧基-2-甲基戊基)氧基)-3-(苯基磺酰基)-1,2,5-噁二唑-2-氧化物(4m)；
4-(4-(羟基氨基)-4-氧代丁氧基)-3-(苯基磺酰基)-1,2,5-噁二唑-2-氧化物(5a)；
4-((5-(羟基氨基)-5-氧代戊基)氧基)-3-(苯基磺酰基)-1,2,5-噁二唑-2-氧化物(5b)；
4-((6-(羟基氨基)-6-氧代己基)氧)-3-(苯基磺酰基)-1,2,5-噁二唑-2-氧化物(5c)；
4-(2-(2-(羟氨基)-2-氧代乙氧基)乙氧基)-3-(苯基磺酰基)-1,2,5-噁二唑-2-氧化物(5d)；
4-(3-(羟基氨基)-2,2-二甲基-3-氧代丙氧基)-3-(苯基磺酰基)-1,2,5-噁二唑-2-氧化物(5e)；
(E)-4-((4-(羟基氨基)-4-氧代丁-2-烯-1-基)氧基)-3-(苯基磺酰基)-1,2,5-噁二唑-2-氧化物(5f)；
4-(4-(羟基氨基甲酰基)苯氧基)-3-(苯基磺酰基)-1,2,5-噁二唑-2-氧化物(5g)；
(E)-4-(4-(3-(羟基氨基)-3-氧代丙-1-烯-1-基)苯氧基)-3-(苯基磺酰基)-1,2,5-噁二唑-2-氧化物(5h)；
4-(3-(羟基氨基甲酰基)苯氧基)-3-(苯基磺酰基)-1,2,5-噁二唑-2-氧化物(5i)；
4-(4-(羟基氨基甲酰基)-2-甲氧基苯氧基)-3-(苯基磺酰基)-1,2,5-噁二唑-2-氧化物(5j)；
4-(4-(2-(羟氨基)-2-氧代乙基)苯氧基)-3-(苯基磺酰基)-1,2,5-噁二唑-2-氧化物(5k)；
4-(2-(2-(2-(羟氨基)-2-氧代乙氧基)乙氧基)乙氧基)-3-(苯基磺酰基)-1,2,5-噁二唑-2-氧化物(5l)；
4-((2-(羟基氨基甲酰基)-2-甲基戊基)氧基)-3-(苯基磺酰基)-1,2,5-噁二唑-2-氧化物(5m)。
二、本发明1,2,5-噁二唑-2-氧化物组蛋白去乙酰化酶抑制剂的制备方法
所述化合物的制备方法，步骤如下：
以苯硫基乙酸为原料，经氧化，硝化反应得到关键中间体2，后经过亲核取代，氧化得到羧酸化合物，最后由盐酸羟胺制成目标产物羟肟酸5；
中间体3经过氧化得到相应的醛6，再经过缩合反应得到相应的不饱和酸7。
合成路线如下：
其中，R1的定义与式I化合物相同。
上述合成路线反应式中的试剂：(a)双氧水，醋酸；(b)发烟硝酸；(c)不同结构的二醇，质量分数25％氢氧化钠水溶液；(d)Jones试剂，丙酮；(e)氯甲酸异丁酯，三乙胺，四氢呋喃；盐酸羟胺，氢氧化钾，甲醇；(f)三氧化铬吡啶盐酸盐，二氯甲烷；(g)丙二酸，四氢吡咯，吡啶。
合成路线的目标化合物结构式如下表1所示：
表1化合物5a-5m结构式
所述化合物制备的具体操作步骤在实例中将加以说明。
本领域技术人员可以对上述步骤进行变动以提高收率，他们可据本领域的基本知识确定合成的路线，如选择反应物，溶剂和温度，可以通过使用各种常规保护基以避免副反应的发生从而提高收率。这些常规的保护方法可参见例如T.Greene，Protecting Groups in OrganicSynthesis。
三、1,2,5-噁二唑-2-氧化物组蛋白去乙酰化酶抑制剂的应用
本发明还提供了上述化合物在制备预防或治疗与组蛋白去乙酰化酶活性异常表达相关的哺乳动物疾病的药物中的应用。所述的与组蛋白去乙酰化酶活性异常表达的相关哺乳动物疾病包括：癌症，神经变性疾病，病毒感染，炎症，白血病，疟疾或糖尿病等。因此，本发明还涉及含有式I结构化合物的药物组合物。
此外，本发明还包括一种适于口服给予哺乳动物的药物组合物，包含上述通式I的化合物，和药学上可接受载体，任选包含一种或多种药学上可接受的赋形剂。
此外，本发明还包括一种适于肠胃外给予哺乳动物的药物组合物，包含上述通式I的化合物，和药学上可接受载体，任选包含一种或多种药学上可接受的赋形剂。由于锌离子依赖性组蛋白去乙酰化酶(HDACs)各亚型催化中心的高度同源性，选择目前已知X-衍射晶体结构的组蛋白去乙酰化酶1和2的混合酶(HDAC1 and 2)，3(HDAC 3)，和6(HDAC 6)来进行酶活性测试。
HDACs活性荧光分析方法(两步法)，能快速、方便检测HDACs活性，操作简单，灵敏度高。第一步含一个乙酰化侧链的赖氨酸HDACs荧光底物Boc-Lys(acetyl)-AMC(Boc-Lys(acetyl)-AMC)，用含表达的HDAC1&2，HDAC3，HDAC6样本孵育，使底物脱去乙酰基，激活底物。第二步，用胰酶水解Boc-Lys-AMC，产生4-氨基-7-甲基-香豆素(AMC)这一荧光基团(即发色团)，在激发波长/发射波长(390nm/460nm)测定荧光强度，从而根据抑制剂组及对照组的荧光强度计算抑制率，并求算出IC50值。酶活性测试原理见如下反应式IV。
化合物的细胞活性的测试使用噻唑兰检测法(MTT法)，人红白细胞白血病细胞(HEL)和人结肠癌细胞(HCT-116)细胞悬液分别接种于96孔板，每孔加入不同浓度化合物的培养基，经孵育后，用MTT染色，继续孵育后，于酶标仪上在570nm处测定每孔的吸光度(OD值)，计算出细胞生长抑制率，从而确定化合物的活性。
通式I的化合物的体外抑酶实验证明该类化合物为一种组蛋白去乙酰化酶抑制剂。
呋咱型NO供体化合物在体内一般通过与各种硫醇类化合物如蛋白质的半胱氨酸残基等反应降解而释放出NO，强亲核试剂RS-离子可进攻Furoxans型化合物中1,2,5-噁二唑-2-氧化物杂环的3-或4-位使其开环形成亚硝基化合物中间体，进而发生消去反应生成NO，生成的NO可被溶液中的O2迅速氧化为亚硝酸根离子(NO2-)和硝酸根离护(NO3-)(见反应式V)。根据上述原理，呋咱型NO供体化合物的体外NO释放实验通常采用在L-cys溶液中37℃孵育的方法进行测定。
Griess法是最经典的NO浓度测定法,其原理是通过测定NO的代谢产物亚硝酸根离子(NO2-)的含量来问接衡量NO的浓度，亚硝酸根离子(NO2-)可与Griess试剂(4％对氨基苯磺酞胺、0.2％N-(l-萘基)乙二胺二盐酸盐、H3PO4)进行重氮-偶氮化反应生成有色的偶氮化合物(见反应式VI)，其在540-560nm范围内有吸收峰,可通过可见光分光光度法测定其吸光度和计算其浓度，该法操作简便,常用于测定NO的体外释放。
采用NO检测试剂盒(碧云天生物技术研究所)，样品为细胞培养液上清，细胞培养液为DMEM+10％FBS，用DMEM+10％FBS稀释标准品，配置标准品的浓度可取0,1,2,5,10,20,40,60,100μM，与540nm出检测吸光度A，以吸光度A为纵坐标，NO2-浓度C做横坐标作图即得标准曲线。采用人红白细胞白血病细胞(HEL)接种于24孔板中，加入配置好的待测化合物的相应浓度孵育后，依次加入试剂盒中的试剂I和试剂II，后在540nm波长下测吸光度(OD)，后带入标准曲线，即可计算出对应的一氧化氮的释放量。
通式I的化合物的细胞内一氧化氮释放实验证明该类化合物可在肿瘤细胞内释放出大量的一氧化氮。
本发明的1,2,5-噁二唑-2-氧化物杂环的衍生物在空间上与组蛋白去乙酰化酶的活性位点相匹配，同时又能释放大量的一氧化氮，因此在体外显示了较高的抑制活性。
四、含有本发明化合物的药物组合物
本发明的部分延伸物可以游离形式或以盐形式存在。本领域技术人员已知许多化合物类型的药学上可接受的盐及其制备方法。药学上可接受的盐包括常规的无毒性的盐，包括这样的化合物碱与无机或有机酸形式的季铵盐。
本发明的化合物可形成水合物或溶剂合物。本领域数熟练人员已知将化合物与水一起冻干时形成的水合物或在溶液中与合适的有机溶剂浓缩时形成溶剂合物的方法。
本发明包含含有治疗量本发明化合物的药物，和一种或多种药学上可接受载体和/或赋形剂的药物组合物。载体包括盐水，缓冲盐水，葡萄糖，水，甘油，乙醇和他们的结合物，下文更详细的论述。如果需要，该组合物还可以包含较小量的润湿剂或乳化剂，或pH缓冲剂。该组合物可以是液体，悬浮液，乳液，片剂，丸剂，胶囊，持续释放制剂或粉末。该组合物可以用传统的黏合剂和载体如三酸甘油酯配置成栓剂。口服制剂可以包括标准载体如药物品级的甘露糖醇，乳糖，淀粉，硬脂酸镁，糖精钠，纤维素和碳酸镁等。视需要制剂而定，配置成可以设计混合，制粒和压缩或溶解成分。在另一途径中，该组合物可以配置成纳米颗粒。
使用的药物载体可以为固体或者液体。
典型的固体载体包括乳糖，石膏粉，蔗糖，滑石，凝胶，琼脂，果胶，阿拉伯胶，硬脂酸镁，硬脂酸等。固体载体可以包括一种或多种可能同时作为增香剂，润滑剂，增溶剂，悬浮剂，填料，助流剂，压缩助剂，粘合剂或片剂-崩解剂的物质；他还可以是包封材料。在粉末中，载体为精细粉碎的固体，它与精细粉碎的活性成分混合。在片剂中活性成分与具有必要的压缩性质的载体以合适的比例混合，以需要的形状和大小压缩。粉末和片剂优选包含至多99％活性成分。合适的固体载体包括，例如，磷酸钙，硬脂酸镁，滑石，糖，乳糖，糊精，淀粉，凝胶，纤维素，甲基纤维素，羧甲基纤维素钠盐，聚乙烯吡咯烷酮，低熔点蜡和离子交换树脂。
典型的液体载体包括糖浆，花生油，橄榄油，水等。押题载体用于制备溶液，悬浮液，乳剂，糖浆，酊剂和密封的组合物。活性成分可以溶解或悬浮于药学上可以接受的液体载体如水，有机溶剂，而这的混合物或药学上可接受的油类或脂肪。液体载体可以包含其他合适的药物添加剂如增溶剂，乳化剂，缓冲剂，防腐剂，增甜剂，增香剂，悬浮剂，增稠剂，颜料，粘度调节剂，稳定形或渗透压-调节剂。用于口服和肠胃外给药的液体载体的合适的例子包括水(部分地包含如同上述的添加剂，例如纤维素衍生物，优选羧甲基纤维素钠盐溶液)，醇(包括一元醇和多元醇，例如乙二醇)和他们的衍生物，和油类(例如分馏椰子油和花生油)。用于肠胃外给药的载体还可以为油脂如油酸乙酯和异丙基肉豆蔻酸盐。无菌的液体载体用于肠胃外给药的无菌的液态组合物。用于加压组合物的液态载体可以为卤代烃或其他药学上可接受的推进剂。无菌溶液或悬浮溶液液体药物组合物可以用来，例如，静脉内，肌内，腹膜内或皮下注射。注射时可单次推入或逐渐注入，入30分钟的经脉内灌注。该化合物还可以以液体或者固体组合物的形式口服给药。
载体或赋形剂可以包括本领域抑制的时间延迟材料，如单硬脂酸甘油酯或二硬脂酸甘油酯，还可包括蜡，乙基纤维素，羟丙基甲基纤维素，异丁烯酸甲酯等。当知己用于口服时，公认PHOSALPG-50(磷酸(phospholipid)与1，2-丙二醇浓缩，A.Nattermann&Cie.GmbH)中的0.01％吐温80用于其他化合物的可接受的口服制剂的配制，可以适应于本发明各种化合物的配制。
给予本发明化合物时可以使用各式各样的药物形式。如果使用固体载体，制剂可以为片剂，被放入硬胶囊中的粉末或小药丸形式或锭剂或糖锭形式。固体载体的量在很大程度上的变化，但是优选从约25mg到约1.0g。如果使用液体载体，制剂可以为糖浆，乳剂，软胶囊，在安或小瓶或非水的液体悬浮液中的无菌注射溶液或悬浮液。
为了获得稳定的水溶性的剂型，可以将化合物或其要学上可接受的盐荣誉有机或无机酸的水溶液，0.3M琥珀酸或柠檬酸溶液。选择性地，酸性的衍生物可以荣誉合适的碱性溶液。如果得不到可溶形式，可将化合物溶于合适的共溶剂或他们的结合。这样的合适的共溶剂的例子包括，但是不局限于，浓度范围从0-60％总体积的乙醇，丙二醇，聚乙二醇300，聚山梨酸酯80，甘油，聚氧乙烯脂肪酸酯，脂肪醇或甘油羟基脂肪酸酯等。
各种释放系统是已知的并且可以用于化合物或其他各种制剂的给药，这些制剂包括片剂，胶囊，可注射的溶液，脂质体中的胶囊，微粒，微胶囊等。引入非方法包括但是不局限于皮肤的，皮内，肌内，腹膜内，静脉内的，皮下的，鼻腔内的，肺的，硬膜外的，眼睛的和(通常优选的)口服途径。化合物可以通过任何方便的或者其他适当的途径给药，例如通过注入或快速浓注，通过上皮的或粘膜线路(例如，口腔黏膜，直肠和肠粘膜等)吸收或通过负载药物的支架以及可以与其他生物活性剂一起给药。可以全身或局部给药。用于鼻，支气管或肺疾病的治疗或预防时，优选的给药途径为口服，鼻给药或支气管烟雾剂或喷雾器。
本发明中的化合物5a，5b，5c，5g对组蛋白去乙酰化酶1&2，3和6亚型(HDAC1&2，HDAC3，HDAC6)的抑制活性与阳性药相当，选择性比阳性药更强，同时可以释放大量的一氧化氮，具有良好的开发前景，并可作为发现新型高效组蛋白去乙酰化酶抑制剂的先导化合物。此外，化合物5a，5b，5c，5g在体外抗肿瘤细胞增殖的试验中显示出一定的活性，值得进一步进行结构优化和开发。
附图说明
图1是目标化合物在HEL细胞内释放一氧化氮的释放量图。
图2是化合物4-((6-(羟基氨基)-6-氧代己基)氧)-3-(苯基磺酰基)-1,2,5-噁二唑-2-氧化物(5c)与组蛋白去乙酰化酶2亚型的活性区域的对接结果通过sybyl18.0以三维显示示意图。
具体实施方式
下面结合实施例对本发明做进一步的说明，但不限于此。
实施例1本发明化合物5a-5m的合成
化合物2的合成：
将苯硫基乙酸(5.0g，27.5mmol)置于反应瓶中，加8mL醋酸室温搅拌下溶解，滴加30％H2O2 6.8mL，加毕，于室温下继续搅拌。一个小时后，TLC检测无原料存在。冰浴条件下向反应瓶中滴加浓硝酸12mL，并控制内温小于20℃。加毕，将装置置于油浴中加热至100℃回流，TLC检测反应进行。3小时后，反应结束，将装置置于室温环境中，有白色结晶析出，过滤得产物。性状：白色结晶，产率：45％。1H NMR(400MHz,CDCl3)δ8.20(t,J＝7.4Hz,4H),7.83(dd,J＝14.3,7.3Hz,2H),7.69(dt,J＝16.1,8.2Hz,4H).
化合物3a的合成：
将化合物2(1.0g，2.7mmol)，1.2mL1,4-丁二醇置于反应瓶中，加10mL四氢呋喃室温搅拌下溶解，并在冰浴下滴加25％NaOH水溶液1.0mL。加毕，于室温下继续搅拌，TLC检测反应进行。20分钟后，反应结束。旋干溶剂，用乙酸乙酯(3×50mL)稀释萃取，并依次用蒸馏水，饱和食盐水洗涤。分离有机相，用无水硫酸钠干燥，旋干乙酸乙酯得粗品，柱层析纯化，洗脱剂V(石油醚：乙酸乙酯)＝6:1，得产物。性状：白色固体，产率：89％。1H NMR(400MHz,CDCl3)δ8.05(d,J＝7.7Hz,2H),7.76(t,J＝7.3Hz,1H),7.62(t,J＝7.6Hz,2H),4.47(t,J＝6.1Hz,2H),3.76(t,J＝6.1Hz,2H),2.07–1.91(m,2H),1.82–1.71(m,2H),1.62(s,1H)。
化合物3b-3m的合成方法与化合物3a的合成方法相同。
化合物3b：白色固体。1H NMR(600MHz,d6-DMSO)δ8.02(d,J＝7.7Hz,2H),7.91(t,J＝7.4Hz,1H),7.76(t,J＝7.5Hz,2H),4.39(t,J＝6.2Hz,2H),3.42(t,J＝6.2Hz,2H),1.79–1.72(m,2H),1.50–1.44(m,2H),1.42–1.37(m,2H).
化合物3c：白色固体。1H NMR(600MHz,d6-DMSO)δ8.02(d,J＝7.7Hz,2H),7.91(t,J＝7.3Hz,1H),7.76(t,J＝7.8Hz,2H),4.38(t,J＝6.3Hz,2H),3.98(t,J＝6.7Hz,2H),1.79–1.71(m,2H),1.58–1.52(m,2H),1.35(d,J＝3.1Hz,2H),1.29(d,J＝3.1Hz,2H).
化合物3d：白色固体。1H NMR(400MHz,CDCl3)δ8.06(d,J＝7.7Hz,2H),7.75(t,J＝7.5Hz,1H),7.61(t,J＝7.8Hz,2H),4.62–4.51(m,2H),3.97–3.89(m,2H),3.81–3.74(m,2H),3.72–3.67(m,2H).
化合物3e：白色固体。1H NMR(400MHz,CDCl3)δ8.04(d,J＝8.0Hz,2H),7.75(t,J＝7.1Hz,1H),7.61(t,J＝7.7Hz,2H),4.23(s,2H),3.55(s,2H),1.05(s,6H).
化合物3f：白色固体。1H NMR(600MHz,CDCl3)δ8.12–8.02(m,2H),7.96–7.87(m,1H),7.81–7.69(m,2H),5.98–5.77(m,2H),4.68(dd,J＝11.5,1.0Hz,2H),4.23–4.11(m,2H).
化合物3g：白色固体。1H NMR(600MHz,CDCl3)δ8.06(d,J＝7.9Hz,2H),7.93(t,J＝7.3Hz,1H),7.78(t,J＝7.6Hz,2H),7.43(d,J＝8.3Hz,2H),7.37(d,J＝8.3Hz,2H),5.27(t,J＝5.7Hz,2H).
化合物3i：白色固体。1H NMR(600MHz,d6-DMSO)δ8.05(d,J＝7.7Hz,2H),7.91(t,J＝7.5Hz,1H),7.77(t,J＝7.8Hz,2H),7.43(t,J＝7.9Hz,1H),7.35(s,1H),7.27(dd,J＝11.4,9.1Hz,2H),5.27(t,J＝5.5Hz,1H),4.54(d,J＝5.1Hz,2H).
化合物3j：白色固体。1H NMR(600MHz,d6-DMSO)δ8.09(d,J＝8.2Hz,2H),7.95(t,J＝7.4Hz,1H),7.81(t,J＝7.7Hz,2H),7.36(d,J＝8.2Hz,1H),7.17(s,1H),6.98(d,J＝8.2Hz,1H),5.31(d,J＝5.7Hz,1H),4.53(d,J＝5.8Hz,2H),3.72(s,3H).
化合物3k：白色固体。1H NMR(600MHz,d6-DMSO)δ8.06(d,J＝8.1Hz,2H),7.92(t,J＝7.4Hz,1H),7.77(t,J＝7.6Hz,2H),7.32(q,J＝8.6Hz,4H),4.66(t,J＝5.1Hz,1H),3.64(dd,J＝12.4,6.3Hz,2H),2.76(t,J＝6.8Hz,2H).
化合物3l：白色固体。1H NMR(600MHz,CDCl3)δ8.03(d,J＝7.6Hz,2H),7.90(d,J＝7.5Hz,1H),7.76(t,J＝7.9Hz,2H),4.53–4.50(m,2H),3.81–3.79(m,2H),3.64–3.61(m,2H),3.57–3.54(m,2H),3.49(d,J＝5.3Hz,2H),3.43(d,J＝5.0Hz,2H).
化合物3m：白色固体。1H NMR(600MHz,CDCl3)δ8.08–8.01(m,2H),7.95–7.86(m,1H),7.76–7.68(m,2H),4.27(dd,J＝172.0,24.7Hz,2H),3.42(dd,J＝127.1,24.7Hz,2H),1.49(s,1H),1.45–1.33(m,4H),0.95(d,J＝8.4Hz,3H),0.91–0.83(m,3H).化合物4a的合成：
将化合物3a(660mg，2.1mmol)置于反应瓶中，加10mL丙酮室温搅拌下溶解，并在冰浴条件下滴加Jones试剂1.1mL。加毕，室温下继续搅拌，TLC检测反应进行。约5小时后，反应结束，过滤掉生成的绿色沉淀物，旋干溶剂，用乙酸乙酯(3×50mL)稀释萃取，并依次用蒸馏水，饱和食盐水洗涤。分离有机相，用无水硫酸钠干燥，旋干乙酸乙酯得粗品，柱层析纯化，洗脱剂V(石油醚:乙酸乙酯)＝1:1，得产物。白色固体，产率：72％。1H NMR(400MHz,CDCl3)δ8.05(d,J＝7.6Hz,2H),7.76(t,J＝7.4Hz,1H),7.62(t,J＝7.8Hz,2H),4.50(t,J＝6.0Hz,2H),2.60(t,J＝7.0Hz,2H),2.26–2.19(m,2H),2.17(s,1H).
化合物4b-4m的合成方法与化合物4a的合成方法相同。
化合物4b：白色固体。1H NMR(600MHz,d6-DMSO)δ12.09(s,1H),8.02(d,J＝8.0Hz,2H),7.90(t,J＝7.4Hz,1H),7.75(t,J＝7.6Hz,2H),4.40(t,J＝6.0Hz,2H),2.30(t,J＝7.3Hz,2H),1.82–1.74(m,2H),1.62(t,J＝6.4Hz,2H).
化合物4c：白色固体。1H NMR(600MHz,d6-DMSO)δ12.04(s,1H),8.04–8.00(m,2H),7.91(t,J＝7.4Hz,1H),7.76(t,J＝7.9Hz,2H),4.38(t,J＝6.2Hz,2H),2.24(t,J＝7.3Hz,2H),1.79–1.71(m,2H),1.58–1.54(m,2H),1.38(dd,J＝15.3,8.0Hz,2H).
化合物4d：白色固体。1H NMR(600MHz,d6-CDCl3)δ8.07(s,2H),7.74(s,1H),7.61(s,2H),4.61(s,2H),4.28(s,2H),4.02(s,2H).
化合物4e：白色固体。1H NMR(600MHz,CDCl3)δ8.12–7.95(m,2H),7.79–7.70(m,1H),7.60(t,J＝7.8Hz,2H),4.43(s,2H),1.41(s,6H).
化合物4f：白色固体。E:1H NMR(600MHz,DMSO)δ12.80(s,1H),8.04(d,J＝8.1Hz,2H),7.90(t,J＝7.4Hz,1H),7.75(t,J＝7.6Hz,2H),6.54–6.47(m,1H),5.97(d,J＝11.6Hz,1H),5.48(dd,J＝4.7,2.2Hz,2H).
化合物4g：白色固体。1H NMR(600MHz,d6-DMSO)δ13.11(s,1H),8.05(t,J＝8.0Hz,4H),7.92(t,J＝7.5Hz,1H),7.77(t,J＝7.9Hz,2H),7.56(d,J＝8.8Hz,2H).
化合物4i：白色固体。1H NMR(600MHz,d6-DMSO)δ13.34(s,1H),8.07(d,J＝7.8Hz,2H),7.99(s,1H),7.92(t,J＝7.4Hz,2H),7.77(t,J＝7.8Hz,2H),7.73–7.69(m,1H),7.64(t,J＝7.9Hz,1H).
化合物4j：白色固体。1H NMR(600MHz,d6-DMSO)δ13.20(s,1H),8.08(d,J＝7.6Hz,2H),7.95(t,J＝7.5Hz,1H),7.81(t,J＝7.9Hz,2H),7.69(d,J＝1.4Hz,1H),7.64(dd,J＝8.4,1.6Hz,1H),7.57(d,J＝8.3Hz,1H),3.75(s,3H).
化合物4k：白色固体。1H NMR(600MHz,d6-DMSO)δ12.33(s,1H),8.04(d,J＝7.8Hz,2H),7.92(t,J＝7.4Hz,1H),7.77(t,J＝7.7Hz,2H),7.37(q,J＝8.8Hz,4H),3.64(s,2H).
化合物4l：白色固体。1H NMR(600MHz,d6-DMSO)δ8.10–8.00(m,2H),7.98–7.88(m,1H),7.78–7.70(m,2H),4.33(s,2H),4.31(t,J＝7.8Hz,2H),3.77(t,J＝7.8Hz,2H),3.52(s,4H).
化合物4m：白色固体。1H NMR(600MHz,d6-DMSO)δ8.07(d,J＝8.9Hz,2H),7.93(t,J＝7.5Hz,1H),7.75(t,J＝7.4Hz,2H),4.85(dd,J＝283.1,12.4Hz,2H),1.67(dt,J＝98.5,7.7Hz,2H),1.46–1.36(m,2H),0.97(s,3H),0.89(t,J＝6.6Hz,3H).
化合物6的合成：
将3g(2.0g，6mmol)置于反应瓶中，加50mL二氯甲烷室温搅拌溶解，冰浴下滴加PCC(2.16g,10mmol)的二氯甲烷溶液。加毕，继续在冰浴下反应，TLC检测反应进程。约5小时后反应结束，用硅藻土过滤掉红棕色固体，蒸干滤液，用乙酸乙酯(3×50mL)稀释萃取，并依次用蒸馏水，饱和食盐水洗涤。分离有机相，用无水硫酸钠干燥，旋干乙酸乙酯得粗品，柱层析纯化，洗脱剂V(石油醚:乙酸乙酯)＝6:1，得产物。白色固体，产率62％。1H NMR(600MHz,DMSO)δ9.98(s,1H),7.95(d,J＝8.5Hz,2H),7.91(d,J＝7.7Hz,2H),7.85(t,J＝7.5Hz,1H),7.70(t,J＝7.9Hz,2H),7.29(d,J＝8.5Hz,2H).
化合物7的合成：
将6(2.5g，8.0mmol)置于反应瓶中，加吡啶室温搅拌溶解后，滴入丙二酸(2.7g,8.0mmol)的吡啶溶液，催化量的四氢吡咯，加毕，加热至120℃回流反应，TLC检测反应进程。4小时后，反应结束，用2N盐酸调pH为中性，并用大量水萃取洗掉吡啶，有机相用无水硫酸钠干燥，旋蒸除去溶剂得粗品，过硅胶柱纯化得产物。白色固体，产率67％。1H NMR(600MHz,DMSO)δ12.47(s,1H),8.05(d,J＝7.8Hz,2H),7.93(t,J＝7.4Hz,1H),7.83(d,J＝8.7Hz,2H),7.77(t,J＝7.8Hz,2H),7.63(d,J＝16.0Hz,1H),7.48(d,J＝8.7Hz,2H),6.57(d,J＝16.0Hz,1H).
化合物5a的合成：
将4a(4g，12.5mmol)置于反应瓶中，加入80mL干燥的四氢呋喃，室温搅拌溶解，后冰浴下滴加氯甲酸异丁酯(3mL)，加毕，冰浴搅拌0.5小时后，滴加三乙胺(3mL)，加毕，于室温下继续搅拌1小时后，过滤除掉生成的沉淀物，留取滤液A。将氢氧化钾(840mg，13mmol)，盐酸羟胺(900mg，13mmol)置于反应瓶中，加mL干燥的甲醇充分溶解，滤掉不溶解的固体，得滤液B。将滤液A滴入滤液B中，继续室温搅拌反应，TLC检测反应进程。4小时后，反应结束，用2N盐酸调pH 3.0左右，旋蒸除掉溶剂，用乙酸乙酯(3×50mL)稀释萃取，并依次用蒸馏水，饱和食盐水洗涤。分离有机相，用无水硫酸钠干燥，旋干乙酸乙酯得粗品，柱层析纯化，洗脱剂V(石油醚:乙酸乙酯)＝1:1，得产物。白色固体，产率：70％。M.p.113-115℃1H NMR(600MHz,DMSO)δ10.51(s,1H),8.80(s,1H),8.03(d,J＝8.2Hz,2H),7.89(t,J＝7.4Hz,1H),7.74(t,J＝7.5Hz,2H),4.40(t,J＝6.2Hz,2H),2.13(t,J＝7.3Hz,2H),2.02–1.97(m,2H).13C NMR(600MHz,DMSO)δ168.79,159.30,137.58,136.61,130.48,128.84,110.98,71.24,63.25,28.62,24.62.HRMS:[M+H+]:实测值m/z 343.0474计算值m/z344.0547
化合物5b-5m的合成方法与化合物5a的合成方法相同。
化合物5b：白色固体。1H NMR(600MHz,d6-DMSO)δ10.39(s,1H),8.74(s,1H),8.02(d,J＝7.9Hz,2H),7.90(t,J＝7.3Hz,1H),7.76(t,J＝7.8Hz,2H),4.38(t,J＝6.1Hz,2H),1.79–1.71(m,2H),1.66–1.58(m,3H),1.53(t,J＝6.8Hz,2H).13C NMR(400MHz,d6-DMSO)δ169.2,159.3,137.6,136.6,130.6,128.8,110.9,71.5,32.1,27.9,21.8.HRMS(ESI)m/z计算值C13H16N3O7S[M+H]+358.0703,实测值358.0705.
化合物5c：白色固体。1H NMR(600MHz,d6-DMSO)δ10.37(s,1H),8.70(s,1H),8.04–7.99(m,2H),7.90(t,J＝7.5Hz,1H),7.76(t,J＝7.9Hz,2H),4.37(t,J＝6.3Hz,2H),1.97(t,J＝7.4Hz,2H),1.78–1.69(m,2H),1.57–1.51(m,2H),1.32(dt,J＝15.3,7.7Hz,2H).13C NMR(400MHz,d6-DMSO)δ169.4,159.3,137.6,136.6,130.5,128.8,110.9,71.8,32.6,28.1,25.2,25.1.HRMS(ESI)m/z计算值C14H18N3O7S[M+H]+372.0860,实测值372.0866.
化合物5d：白色固体。1H NMR(600MHz,d6-DMSO)δ10.54(s,1H),8.89(s,1H),8.03(d,J＝7.5Hz,2H),7.90(t,J＝7.5Hz,1H),7.75(t,J＝7.9Hz,2H),4.58–4.49(m,2H),3.97(s,2H),3.86–3.80(m,2H).13C NMR(400MHz,d6-DMSO)δ171.0,158.8,137.2,136.0,129.9,128.2,110.4,72.1,70.6,68.9,68.2,42.8.HRMS(ESI)m/z计算值C12H14N3O8S[M+H]+360.0496,实测值360.0497.
化合物5e：白色固体。1H NMR(600MHz,d6-DMSO)δ10.61(s,1H),8.81(s,1H),7.99(d,J＝7.5Hz,2H),7.90(t,J＝6.8Hz,1H),7.76(t,J＝7.4Hz,2H),4.38(s,2H),1.22(s,6H).13CNMR(400MHz,d6-DMSO)δ171.4,159.3,137.9,136.5,130.6,130.6,128.62,110.7,76.99,41.7,22.2.HRMS(ESI)m/z计算值C13H16N3O7S[M+H]+358.0704,实测值358.0703.
化合物5f：白色固体。1H NMR(600MHz,DMSO)δ8.10(d,J＝7.5Hz,2H),7.86(t,J＝7.5Hz,1H),7.73(t,J＝7.9Hz,2H),6.96(dt,J＝15.3,4.3Hz,1H),6.27(d,J＝15.5Hz,1H),5.15(d,J＝3.1Hz,2H).13C NMR(400MHz,d6-DMSO)δ161.2,158.6,139.1,136.0,129.9,128.2,120.4,76.7,69.0.HRMS(ESI)m/z calcd for C12H12N3O7S[M+H]+342.0390,found 342.0393.化合物5g：白色固体。1H NMR(600MHz,d6-DMSO)δ11.29(s,1H),9.10(s,1H),8.04(d,J＝7.3Hz,2H),7.93(t,J＝6.8Hz,1H),7.87(d,J＝7.9Hz,2H),7.77(t,J＝7.4Hz,2H),7.52(d,J＝8.0Hz,2H).13C NMR(400MHz,d6-DMSO)δ163.6,158.5,155.1,137.3,136.8,131.4,130.5,129.5,129.1,119.9,111.8.HRMS(ESI)m/z计算值C15H12N3O7S[M+H]+378.0390,实测值378.0439.
化合物5h：白色固体。1H NMR(400MHz,d6-DMSO)δ10.79(s,1H),9.08(s,1H),7.91(d,J＝8.5Hz,1H),7.76(dd,J＝25.3,7.9Hz,2H),7.63(d,J＝8.4Hz,2H),7.47(d,J＝15.9Hz,1H),7.34(dd,J＝15.9,8.4Hz,2H),7.29(d,J＝8.5Hz,2H),6.44(d,J＝15.8Hz,1H).13C NMR(400MHz,d6-DMSO)δ163.3,158.7,138.3,129.0,125.8,115.6,115.4.HRMS(ESI)m/z计算值C14H18N3O9S[M+H]+404.0758,实测值404.0755.
化合物5i：白色固体。1H NMR(400MHz,d6-DMSO)δ11.31(s,1H),9.16(s,1H),8.04(d,J＝7.6Hz,2H),7.92(d,J＝7.4Hz,1H),7.78–7.72(m,4H),7.62–7.57(m,2H).13C NMR(400MHz,d6-DMSO)δ167.3,157.6,144.0,135.4,129.8,119.0,118.9,117.3,114.4.HRMS(ESI)m/z计算值C15H12N3O7S[M+H]+378.0390,实测值378.0378.
化合物5j：白色固体。1H NMR(600MHz,d6-DMSO)δ11.26(s,1H),9.07(s,1H),8.09(d,J＝7.8Hz,2H),7.95(t,J＝7.4Hz,1H),7.81(t,J＝7.6Hz,2H),7.57(s,1H),7.52(d,J＝8.2Hz,1H),7.44(d,J＝8.5Hz,1H),3.79(s,3H).13C NMR(400MHz,d6-DMSO)δ163.0,158.4,149.4,142.8,137.0,136.4,130.2,128.4,121.6,119.8,112.1,110.8,56.3.HRMS(ESI)m/z计算值C16H14N3O8S[M+H]+408.0496,实测值408.0500.
化合物5k：白色固体。1H NMR(600MHz,d6-DMSO)δ10.62(s,1H),8.79(s,1H),8.04(d,J＝7.8Hz,2H),7.92(t,J＝7.4Hz,1H),7.77(t,J＝7.6Hz,2H),7.35(dd,J＝17.3,8.6Hz,4H),3.34(s,2H).13C NMR(400MHz,d6-DMSO)δ158.3,136.9,136.1,131.3,130.4,129.9,129.5,128.5,128.3,119.3,29.9.HRMS(ESI)m/z计算值C16H14N3O7S[M+H]+392.0547,实测值392.0550.
化合物5l：白色固体。1H NMR(600MHz,d6-DMSO)δ10.40(s,1H),8.77(s,1H),8.03(d,J＝7.8Hz,2H),7.91(t,J＝7.4Hz,1H),7.76(t,J＝7.3Hz,2H),4.54–4.50(m,2H),3.89(s,2H),3.84–3.80(m,2H),3.65(d,J＝3.0Hz,2H),3.61(d,J＝3.2Hz,2H).13C NMR(400MHz,d6-DMSO)δ165.5,158.8,137.2,136.0,129.9,128.1,70.8,70.2,69.62,68.9,67.7.HRMS(ESI)m/z计算值C17H14N3O7S[M+H]+404.0547,实测值404.0549.
化合物5m：白色固体。1H NMR(600MHz,DMSO)δ10.63(s,1H),8.79(s,1H),8.04(d,J＝7.5Hz,2H),7.92(t,J＝7.5Hz,1H),7.77(t,J＝7.7Hz,2H),7.35(dd,J＝17.9,8.4Hz,4H),3.34(s,2H).13C NMR(400MHz,d6-DMSO)177.2,172.4,131.3,129.96,129.5,128.5,67.0,64.9,47.2,36.3,35.7,19.8,17.7,13.7.HRMS(ESI)m/z计算值C15H20N3O7S[M+H]+386.1016,实测值386.1017.
实施例2目标化合物抑制细胞增殖的活性实验(In vitro)
选取以上表1中的化合物进行体外抑制癌细胞增殖的活性实验，结果见表2.
术语说明：
HEL：人红白细胞白血病细胞
HCT-116：人结直肠癌细胞
Hela：宫颈癌细胞
U937：组织细胞淋巴瘤细胞
3-AO：人卵巢癌细胞
MDA：人乳腺癌细胞
ES-2：人卵巢透明细胞癌细胞
KG1：白血病细胞株
SAHA：商品名Zolinza，通用名为Vorinostat，为美国食品药品监督管理局(FDA)于2006年批准上市的组蛋白去乙酰化酶抑制剂。
DMSO：二甲基亚砜
IC50：半数抑制浓度
1.[材料]HEL，HCT-116，Hela，U937，3-AO，MDA，ES-2，KG1细胞株，四甲基偶氮唑蓝MTT，10％胎牛血清，96孔板。
2.[方法]
细胞培养以上肿瘤细胞株都采用常规培养。试验时均用对数生长期细胞。
细胞生长检测(MTT法)以上细胞调整至1×105/mL，分别接种于96孔板(100μL/孔)，5000个细胞/孔。铺板24小时后，每孔中加入100μL含不同浓度化合物的培养基，使孔中化合物终浓度分别为100，20，4，0.8，0.16μM，每个浓度设三个复孔，不加细胞的孔读数时做空白，加细胞不加化合物的孔做化合物空白孔，SAHA做化合物阳性对照。于37℃，5％二氧化碳中孵育48小时，每孔加入20μL0.5％MTT染色液，继续孵育4小时后，抛弃板中的培养基，加入二甲基亚砜20050μL/孔。酶标仪上于490，630nm波长处测定每孔的吸光度值，细胞生长抑制率按下式计算：
表2细胞增殖实验结果
a标准数值均为三次试验的平均值。
上表检测数据表明化合物5a，5b，5c，5g在体外抗肿瘤细胞增殖的试验中显示出一定的活性，值得进一步的抑制酶活性和一氧化氮释放的实验。
实施例3化合物5a，5b，5c，5g抑制组蛋白去乙酰化酶活性实验(In vitro)
采用HDACs活性荧光分析方法进行酶活性实验，主要分两步：(1)含一个乙酰化侧链的赖氨酸HDACs荧光底物(Boc-Lys(acetyl)-AMC)，用含表达的HDAC8的样本孵育，使底物脱去乙酰基，激活底物。(2)用胰酶水解含一个乙酰化侧脸的赖氨酸HDACs荧光底物(Boc-Lys-AMC)，产生AMC这一荧光基团，在激发波长/发射波长(390nm/460nm)测定荧光强度，从而根据抑制剂组及对照组的荧光强度计算抑制率，并求算IC50值。酶活性测试原理见前述反应式IV及相关内容。实验结果见表3。
表3化合物5a，5b，5c，5g的体外实验结果
a表中数值为三次试验的平均值。
SAHA商品名Zolinza，通用名为Vorinostat，为美国食品药品监督管理局(FDA)于2006年批准上市的组蛋白去乙酰化酶抑制剂。
上述测试结果表明，1,2,5-噁二唑-2-氧化物衍生物化合物抑制细胞增殖较强的化合物均表现出对组蛋白去乙酰化酶1&2，3，6亚型(HDAC1&2，HDAC3，HDAC6)较强的抑制活性，具有良好的开发前景，并可作为发现新型高效组蛋白去乙酰化酶抑制剂的先导化合物。
实施例4目标化合物一氧化氮释放检测试验(In vitro)
参照NO检测试剂盒(碧云天生物技术研究所)说明要求做标准曲线。
选择HEL细胞调整至1×105/mL，接种于24孔板(2mL/孔)，50×104个细胞/孔。每孔中加入2μL含100mM化合物的培养基，使孔中化合物终浓度分别为，每个化合物设三个复孔，空白孔加2μL二甲基亚砜SAHA做化合物阳性对照。于37℃，5％二氧化碳中孵育3或5小时。收集三个复孔的培养基，离心1200rm，弃上清留取细胞，加200μL细胞裂解液裂解细胞30分钟。1200rm离心，取50μL/孔上清液置于96孔板中，做3个复孔。依次加入试剂盒中的试剂I50μL/孔和试剂II50μL/孔，于37℃，5％二氧化碳中孵育15分钟，，在激发波长(540nm)测定荧光强度，并根据对照组和空白组计算其OD值，带入标准曲线，计算出一氧化氮的释放量。实验结果见图1。
上述实验表明，本发明中合成的化合物均能够产生较大量的NO，特别是化合物5c，即表明本发明中涉及的化合物可以作为NO供体。
Claims (6)
1.1,2,5-噁二唑-2-氧化物组蛋白去乙酰化酶抑制剂，具有通式I所示的结构；
其中，
X是氧；
R1是C1-8的饱和脂肪链或苯基；
R2是异羟肟酸；
R3是砜基。
2.1,2,5-噁二唑-2-氧化物组蛋白去乙酰化酶抑制剂，其特征在于，是下列化合物之一：
4-(4-(羟基氨基)-4-氧代丁氧基)-3-(苯基磺酰基)-1,2,5-噁二唑-2-氧化物(5a)；
4-((5-(羟基氨基)-5-氧代戊基)氧基)-3-(苯基磺酰基)-1,2,5-噁二唑-2-氧化物(5b)；
4-((6-(羟基氨基)-6-氧代己基)氧)-3-(苯基磺酰基)-1,2,5-噁二唑-2-氧化物(5c)；
4-(2-(2-(羟氨基)-2-氧代乙氧基)乙氧基)-3-(苯基磺酰基)-1,2,5-噁二唑-2-氧化物(5d)；
4-(3-(羟基氨基)-2,2-二甲基-3-氧代丙氧基)-3-(苯基磺酰基)-1,2,5-噁二唑-2-氧化物(5e)；
(E)-4-((4-(羟基氨基)-4-氧代丁-2-烯-1-基)氧基)-3-(苯基磺酰基)-1,2,5-噁二唑-2-氧化物(5f)；
4-(4-(羟基氨基甲酰基)苯氧基)-3-(苯基磺酰基)-1,2,5-噁二唑-2-氧化物(5g)；
(E)-4-(4-(3-(羟基氨基)-3-氧代丙-1-烯-1-基)苯氧基)-3-(苯基磺酰基)-1,2,5-噁二唑-2-氧化物(5h)；
4-(3-(羟基氨基甲酰基)苯氧基)-3-(苯基磺酰基)-1,2,5-噁二唑-2-氧化物(5i)；
4-(4-(羟基氨基甲酰基)-2-甲氧基苯氧基)-3-(苯基磺酰基)-1,2,5-噁二唑-2-氧化物(5j)；
4-(4-(2-(羟氨基)-2-氧代乙基)苯氧基)-3-(苯基磺酰基)-1,2,5-噁二唑-2-氧化物(5k)；
4-(2-(2-(2-(羟氨基)-2-氧代乙氧基)乙氧基)乙氧基)-3-(苯基磺酰基)-1,2,5-噁二唑-2-氧化物(51)；
4-((2-(羟基氨基甲酰基)-2-甲基戊基)氧基)-3-(苯基磺酰基)-1,2,5-噁二唑-2-氧化物(5m)。
3.权利要求1所述化合物的制备方法，其特征在于包括如下步骤：
以苯硫基乙酸为原料，经氧化，硝化反应得到关键中间体2，后经过亲核取代，氧化得到羧酸化合物，最后由盐酸羟胺制成目标产物羟肟酸5；合成路线如下：
其中，R1的定义与权利要求1中式I化合物相同；
上述合成路线反应式中的试剂：(a)双氧水，醋酸；(b)发烟硝酸；(c)不同结构的二醇，质量分数25％氢氧化钠水溶液；(d)琼斯试剂，丙酮；(e)氯甲酸异丁酯，三乙胺，四氢呋喃；盐酸羟胺，氢氧化钾，甲醇。
4.权利要求1或2所述的化合物在制备预防或治疗与组蛋白去乙酰化酶活性异常表达相关的哺乳动物疾病的药物中的应用；所述的与组蛋白去乙酰化酶活性异常表达的相关哺乳动物疾病包括：癌症，神经变性疾病，病毒感染，炎症，疟疾或糖尿病。
5.一种适于口服给予哺乳动物的药物组合物，包含权利要求1或2所述的化合物和一种或多种药学上可接受载体或赋形剂。
6.一种适于胃肠外给予哺乳动物的药物组合物，包含权利要求1或2所述的化合物和一种或多种药学上可接受载体或赋形剂。
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| CN106794175B (zh) * | 2014-06-12 | 2020-06-09 | 西达-赛奈医疗中心 | 用于治疗癌症的组合物 |
| CN104119289B (zh) * | 2014-07-16 | 2016-08-17 | 成都丽凯手性技术有限公司 | 一种合成氧化呋咱化合物的方法 |
| CN104356087B (zh) * | 2014-10-11 | 2016-01-13 | 南通大学附属医院 | 一氧化氮供体型hdac抑制剂及其制备方法和医药用途 |
| CN106279058B (zh) * | 2015-06-08 | 2019-07-26 | 沈阳药科大学 | 3,4-二芳基-1,2,5-噁二唑氧化物的制备及用途 |
| CN115043824B (zh) * | 2021-03-09 | 2024-04-02 | 上海交通大学医学院 | 具有抑制sirt6去乙酰化活性的化合物、sirt6抑制剂及其应用 |
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