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单(3-丁基-8-(9-羧基-6-羟基-3,7-二甲基-2,4,8-壬三烯基)-2-(4-羧基-3-甲基-1,3-丁二烯基)-9-甲基-1,7-二氧杂螺(5.5)十一碳-3-基)丁二酸酯 | 134615-37-5

分子结构分类

有机化合物 - 脂质和类脂质分子 - 异戊烯醇脂质

中文名称

单(3-丁基-8-(9-羧基-6-羟基-3,7-二甲基-2,4,8-壬三烯基)-2-(4-羧基-3-甲基-1,3-丁二烯基)-9-甲基-1,7-二氧杂螺(5.5)十一碳-3-基)丁二酸酯

中文别名

雷弗霉素A

英文名称

Reveromycin A

英文别名

(-)-reveromycin A；(2E,4S,5S,6E,8E)-10-[(2S,3R,6S,8R,9S)-3-butyl-2-[(1E,3E)-4-carboxy-3-methylbuta-1,3-dienyl]-3-(3-carboxypropanoyloxy)-9-methyl-1,7-dioxaspiro[5.5]undecan-8-yl]-5-hydroxy-4,8-dimethyldeca-2,6,8-trienoic acid

单(3-丁基-8-(9-羧基-6-羟基-3,7-二甲基-2,4,8-壬三烯基)-2-(4-羧基-3-甲基-1,3-丁二烯基)-9-甲基-1,7-二氧杂螺(5.5)十一碳-3-基)丁二酸酯化学式

CAS

134615-37-5

化学式

C₃₆H₅₂O₁₁

mdl

——

分子量

660.802

InChiKey

ZESGNAJSBDILTB-OXVOKJAASA-N

BEILSTEIN

——

EINECS

——

物化性质

沸点：

849.0±65.0 °C(Predicted)
密度：

1.21±0.1 g/cm3(Predicted)
溶解度：

在DMF中可溶

计算性质

辛醇/水分配系数(LogP)：

5.9
重原子数：

47
可旋转键数：

18
环数：

2.0
sp3杂化的碳原子比例：

0.61
拓扑面积：

177
氢给体数：

4
氢受体数：

11

安全信息

储存条件：

-20°C，干燥且密封保存。

SDS

SDS：c1e04a76ad068ec7fd9fb780fca922e8

查看

制备方法与用途

生物活性

Reveromycin A 是一种从链霉菌属中分离出来的苯甲醌类抗生素，是选择性的真核细胞蛋白质合成抑制剂。它通过诱导破骨细胞凋亡来抑制骨吸收，并对肿瘤细胞系具有抗增殖活性，同时具备抗真菌活性。

体外研究

Reveromycin A 能通过特异性地阻断异亮酰-tRNA 合成酶的酶促活性来抑制破骨细胞（OCs）中的蛋白质合成。浓度在 0.3-30 μM 的 Reveromycin A 经过 24 小时处理后，能通过抑制蛋白质合成诱导 OCs 凋亡。

体内研究

在正常 4 周龄雄性 Sprague-Dawley 大鼠中，使用剂量为 20 mg/kg、每日两次腹腔注射 3 天的 Reveromycin A 显著减少了破骨细胞的数量，而未影响成骨细胞的数量。

上下游信息

上游原料

中文名称	英文名称	CAS号	化学式	分子量
——	4-O-[(2S,3R,6S,8R,9S)-3-butyl-9-methyl-8-[(E)-3-methyl-4-oxobut-2-enyl]-2-[(1E,3E)-3-methyl-5-oxo-5-prop-2-enoxypenta-1,3-dienyl]-1,7-dioxaspiro[5.5]undecan-3-yl] 1-O-prop-2-enyl butanedioate	297741-48-1	C₃₅H₅₀O₉	614.777
——	4-O-[(2S,3R,6S,8R,9S)-3-butyl-8-(2-hydroxyethyl)-9-methyl-2-[(1E,3E)-3-methyl-5-oxo-5-prop-2-enoxypenta-1,3-dienyl]-1,7-dioxaspiro[5.5]undecan-3-yl] 1-O-prop-2-enyl butanedioate	297741-43-6	C₃₂H₄₈O₉	576.728
——	(2E,4S,5S,6E,8E)-10-[(2S,3R,6S,8R,9S)-3-butyl-2-[(1E,3E)-4-carboxy-3-methylbuta-1,3-dienyl]-3-(3-carboxypropanoyloxy)-9-methyl-1,7-dioxaspiro[5.5]undecan-8-yl]-5-[tert-butyl(dimethyl)silyl]oxy-4,8-dimethyldeca-2,6,8-trienoic acid	479692-43-8	C₄₂H₆₆O₁₁Si	775.065
——	4-O-[(2S,3R,6S,8R,9S)-3-butyl-8-[(2E,4E,6S,7S,8E)-6-[tert-butyl(dimethyl)silyl]oxy-3,7-dimethyl-10-oxo-10-prop-2-enoxydeca-2,4,8-trienyl]-9-methyl-2-[(1E,3E)-3-methyl-5-oxo-5-prop-2-enoxypenta-1,3-dienyl]-1,7-dioxaspiro[5.5]undecan-3-yl] 1-O-prop-2-enyl butanedioate	297741-53-8	C₅₁H₇₈O₁₁Si	895.259
——	4-O-[(2S,3R,6S,8R,9S)-3-butyl-8-[(2E,4E,6S,7S,8E)-6-[tert-butyl(dimethyl)silyl]oxy-3,7-dimethyl-10-oxo-10-(2-trimethylsilylethoxy)deca-2,4,8-trienyl]-9-methyl-2-[(1E,3E)-3-methyl-5-oxo-5-(2-trimethylsilylethoxy)penta-1,3-dienyl]-1,7-dioxaspiro[5.5]undecan-3-yl] 1-O-(2-trimethylsilylethyl) butanedioate	757192-11-3	C₅₇H₁₀₂O₁₁Si₄	1075.77
——	Succinic acid allyl ester (2S,3R,6S,8R,9S)-2-((1E,3E)-4-allyloxycarbonyl-3-methyl-buta-1,3-dienyl)-3-butyl-8-[(2E,4E)-(6S,7R)-6-(tert-butyl-dimethyl-silanyloxy)-3,7-dimethyl-8-oxo-octa-2,4-dienyl]-9-methyl-1,7-dioxa-spiro[5.5]undec-3-yl ester	297741-52-7	C₄₆H₇₂O₁₀Si	813.157
——	4-O-[(2S,3R,6S,8R,9S)-3-butyl-8-[(2E,4E,6S,7S)-6-[tert-butyl(dimethyl)silyl]oxy-3,7-dimethyl-8-triethylsilyloxyocta-2,4-dienyl]-9-methyl-2-[(1E,3E)-3-methyl-5-oxo-5-prop-2-enoxypenta-1,3-dienyl]-1,7-dioxaspiro[5.5]undecan-3-yl] 1-O-prop-2-enyl butanedioate	297741-51-6	C₅₂H₈₈O₁₀Si₂	929.436
——	4-O-[(2S,3R,6S,8R,9S)-3-butyl-8-[(2E,4E,6S,7S)-6-[tert-butyl(dimethyl)silyl]oxy-8-hydroxy-3,7-dimethylocta-2,4-dienyl]-9-methyl-2-[(1E,3E)-3-methyl-5-oxo-5-(2-trimethylsilylethoxy)penta-1,3-dienyl]-1,7-dioxaspiro[5.5]undecan-3-yl] 1-O-(2-trimethylsilylethyl) butanedioate	757192-10-2	C₅₀H₉₀O₁₀Si₃	935.515
——	4-O-[(2S,3R,6S,8R,9S)-8-[(E)-4-(1,3-benzothiazol-2-ylsulfonyl)-3-methylbut-2-enyl]-3-butyl-9-methyl-2-[(1E,3E)-3-methyl-5-oxo-5-prop-2-enoxypenta-1,3-dienyl]-1,7-dioxaspiro[5.5]undecan-3-yl] 1-O-prop-2-enyl butanedioate	297741-50-5	C₄₂H₅₅NO₁₀S₂	798.031

下游产品

中文名称	英文名称	CAS号	化学式	分子量
——	reveromycin A 4'-methyl ester	——	C₃₇H₅₄O₁₁	674.829
——	reveromycin A trimethyl ester	479692-44-9	C₃₉H₅₈O₁₁	702.883
——	(2E,4S,5S,6E,8E)-10-[(2S,3R,6S,8R,9S)-3-butyl-2-[(1E,3E)-4-carboxy-3-methylbuta-1,3-dienyl]-3-methoxy-9-methyl-1,7-dioxaspiro[5.5]undecan-8-yl]-5-hydroxy-4,8-dimethyldeca-2,6,8-trienoic acid	——	C₃₃H₅₀O₈	574.755
——	(2E,4S,5S,6E,8E)-10-[(2S,3R,6S,8R,9S)-3-butyl-2-[(1E,3E)-4-carboxy-3-methylbuta-1,3-dienyl]-3-(3-carboxypropanoyloxy)-9-methyl-1,7-dioxaspiro[5.5]undecan-8-yl]-5-[tert-butyl(dimethyl)silyl]oxy-4,8-dimethyldeca-2,6,8-trienoic acid	479692-43-8	C₄₂H₆₆O₁₁Si	775.065
——	(2E,4S,5S,6E,8E)-10-[(2S,3R,6S,8R,9S)-3-butyl-2-[(1E,3E)-4-carboxy-3-methylbuta-1,3-dienyl]-3-hydroxy-9-methyl-1,7-dioxaspiro[5.5]undecan-8-yl]-5-hydroxy-4,8-dimethyldeca-2,6,8-trienoic acid	479692-52-9	C₃₂H₄₈O₈	560.728
——	(2E,6E,8E)-(4S,5S)-5-(tert-Butyl-dimethyl-silanyloxy)-10-[(2R,3S,6S,8S,9R)-9-butyl-9-hydroxy-8-((1E,3E)-4-methoxycarbonyl-3-methyl-buta-1,3-dienyl)-3-methyl-1,7-dioxa-spiro[5.5]undec-2-yl]-4,8-dimethyl-deca-2,6,8-trienoic acid methyl ester	479692-54-1	C₄₀H₆₆O₈Si	703.045

反应信息

作为反应物：

描述：

单(3-丁基-8-(9-羧基-6-羟基-3,7-二甲基-2,4,8-壬三烯基)-2-(4-羧基-3-甲基-1,3-丁二烯基)-9-甲基-1,7-二氧杂螺(5.5)十一碳-3-基)丁二酸酯在 lithium hydroxide 作用下，以96%的产率得到(2E,4S,5S,6E,8E)-10-[(2S,3R,6S,8R,9S)-3-butyl-2-[(1E,3E)-4-carboxy-3-methylbuta-1,3-dienyl]-3-hydroxy-9-methyl-1,7-dioxaspiro[5.5]undecan-8-yl]-5-hydroxy-4,8-dimethyldeca-2,6,8-trienoic acid

参考文献：

名称：

Reveromycin A的化学修饰及其生物学活性。

摘要：

制备了多种真核细胞生长抑制剂Reveromycin A，并测定了它们对异亮氨酰-tRNA合成酶活性和体外蛋白质合成的抑制作用，以及对src（ts）-NRK细胞形态回复的活性。对于这些活性，C 5羟基和C 24羧基特别重要。

DOI：

10.1016/s0960-894x(02)00782-5
作为产物：

描述：

methyl (2E,4E)-6-[(2S,3R,6S,8R,9S)-3-butyl-3-[tert-butyl(dimethyl)silyl]oxy-2-ethynyl-9-methyl-1,7-dioxaspiro[5.5]undecan-8-yl]-4-methylhexa-2,4-dienoate 在 bis-triphenylphosphine-palladium(II) chloride N-乙基哌啶、咪唑、 4-二甲氨基吡啶、 sodium tetrahydroborate 、 tin(II) trifluoromethanesulfonate 、四丁基氟化铵、三正丁基氢锡、二异丁基氢化铝、戴斯-马丁氧化剂、氟化氢吡啶、 N,N'-二环己基碳二亚胺作用下，以四氢呋喃、吡啶、二氯甲烷、水、 N,N-二甲基甲酰胺为溶剂， 50.0~60.0 ℃ 、400.0 MPa 条件下，生成单(3-丁基-8-(9-羧基-6-羟基-3,7-二甲基-2,4,8-壬三烯基)-2-(4-羧基-3-甲基-1,3-丁二烯基)-9-甲基-1,7-二氧杂螺(5.5)十一碳-3-基)丁二酸酯

参考文献：

名称：

Total Synthesis of (−)-Reveromycin A

摘要：

The asymmetric total synthesis of (-)-reveromycin A is described. The key steps involved a Lewis acid catalyzed inverse electron demand hetero-Diels-Alder reaction followed by hydroboration/oxidation to afford the spiroketal core 4 in a highly stereoselective manner and introduction of the C18 hemisuccinate by high-pressure acylation.

DOI：

10.1021/ol048811l

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文献信息

Synthesis and biological activities of reveromycin A and spirofungin A derivatives

作者：Takeshi Shimizu、Takeo Usui、Makoto Fujikura、Makoto Kawatani、Tomoharu Satoh、Kiyotaka Machida、Naoki Kanoh、Je-Tae Woo、Hiroyuki Osada、Mikiko Sodeoka

DOI：10.1016/j.bmcl.2008.05.054

日期：2008.7

Various derivatives of reveromycin A, an inhibitor of eukaryotic cell growth, and spirofungin A, focusing on the 5S hydroxyl group and C18 hemisuccinyl group, were synthesized and their inhibitory effects on both the isoleucyl-tRNA synthetase activity and the survival of osteoclasts, and activities on the morphological reversion of src(ts)-NRK cells were examined. It was found that 2,3-dihydroreveromycin

合成了真核细胞生长抑制剂Reveromycin A和螺菌素A的各种衍生物，它们分别着重于5S羟基和C18半琥珀酰基团，并且它们对异亮氨酰tRNA合成酶的活性以及破骨细胞的存活以及活性的抑制作用对src（ts）-NRK细胞的形态逆转进行了研究。基于活性和稳定性，发现2，3-二氢阿维霉素A是白霉素A的有前途的衍生物。
Total Synthesis of (-)-Reveromycin A via a Hetero-Diels-Alder Approach

作者：Mark Rizzacasa、Mariana El Sous、Danny Ganame、Peter Tregloan

DOI：10.1055/s-0030-1258308

日期：2010.12

The asymmetric total synthesis of (-)-reveromycin A is described which utilizes a Lewis acid catalyzed inverse electron demand hetero-Diels-Alder reaction followed by hydroboration/oxidation to afford the labile [6,6]-spiroketal core in a highly stereoselective manner. An asymmetric syn-aldol reaction installed the stereochemistry at C4-C5 whilst a Stille cross coupling was utilized to form the C21-C22 bond. The C18 hemisuccinate was formed by high pressure acylation reaction and a final Wittig extension followed by global deprotection with tetrabutylammonium fluoride gave (-)-reveromycin A.

(-)-reveromycin A的不对称全合成方法如下：首先通过Lewis酸催化的反向电子需求杂-Diels-Alder反应，接着进行氢硼化/氧化反应，高立体选择性地获得不稳定的[6,6]-螺内酯核心结构。通过不对称顺式醛醇反应确定C4-C5的立体化学结构，而利用Stille交叉偶联反应形成C21-C22键。通过高压酰化反应形成C18半琥珀酸酯，最后进行Wittig扩展和四丁基氟化铵的全保护基去保护，得到(-)-reveromycin A。
Absolute configuration of reveromycin A, an inhibitor of the signal transduction of epidermal growth factor

作者：Makoto Ubukata、Hiroyuki Koshino、Hiroyuki Osada、Kiyoshi Isono

DOI：10.1039/c39940001877

日期：——

The absolute configuration of reveromycin A, a new inhibitor of the signal transduction of epidermal growth factor (EGF), is determined on the basis of chemical degradation and spectroscopic evidence.

基于化学降解和光谱证据，确定了表皮生长因子（EGF）信号转导的新型抑制剂瑞维莫司A的绝对构象。
Total Synthesis of Reveromycin A

作者：Takeshi Shimizu、Tsutomu Masuda、Katsuya Hiramoto、Tadashi Nakata

DOI：10.1021/ol0060634

日期：2000.7.1

[GRAPHICS]The stereoselective total synthesis of reveromycin A (1), a potent inhibitor of eukaryotic cell growth, has been accomplished on the basis of the stereocontrolled construction of the 6,6-spiroketal system, efficient succinylation of the tert alcohol under high pressure, and the introduction of the unsaturated side chains.
PROCESS FOR PRODUCING REVEROMYCIN A OR A SYNTHETIC INTERMEDIATE THEREOF, PROCESS FOR PRODUCING COMPOUNDS CONTAINING A SPIROKETAL RING AND NOVEL ANTINEOPLASTICS, FUNGICIDES AND THERAPEUTIC AGENTS FOR BONE DISORDERS

申请人：Osada Hiroyuki

公开号：US20130177950A1

公开（公告）日：2013-07-11

A bacterium belonging to the genus Streptomyces having an ability to produce reveromycin A or a synthetic intermediate thereof, the bacterium being modified so as to increase expression of revQ gene coding for the amino acid sequence of SEQ ID NO: 36 or an amino acid sequence having an identity of not less than 80% to SEQ ID NO: 36 as compared with a parent strain, thereby the above-mentioned production ability is increased as compared with the parent strain.