Rational design and synthesis of androgen receptor-targeted nonsteroidal anti-androgen ligands for the tumor-specific delivery of a doxorubicin-formaldehyde conjugate
Rational design and synthesis of androgen receptor-targeted nonsteroidal anti-androgen ligands for the tumor-specific delivery of a doxorubicin-formaldehyde conjugate
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DOI：
10.1021/jm0303305
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发表时间：
2003-11-20
影响因子：
7.3
通讯作者：
Koch, TH
中科院分区：
文献类型：
--
作者：
Cogan, PS;Koch, TH
本文报道了一种与非甾体抗雄激素药物氰尼鲁米特（RU 56279）结合的阿霉素-甲醛偶联物的合成和初步评价，用于治疗前列腺癌。研究了靶向基团与人雄激素受体结合的相对能力作为系链的函数。系链用于通过水杨酰胺衍生物的N-曼尼希碱将抗雄激素连接到多柔比星-甲醛缀合物。选择水杨酰胺作为触发释放机制，以在多柔比星-甲醛缀合物与雄激素受体结合后将其与靶向基团分离。系链的剩余部分由从水杨酰胺的5-位跨越到氰尼鲁米特的X-位的线性基团组成。对系链的线性区域探索的结构是二（乙二醇）、三（乙二醇）、N，N '-二取代哌嗪和2-丁炔-1，4-二醇的衍生物。使用3 H-米勃龙竞争测定法测量与人雄激素受体靶向基团结合的系链的相对结合亲和力，并且从基于丁炔二醇的线性区域的尼鲁米特结合的18%到哌嗪衍生物之一的小于1%变化。具有基于丁炔二醇的线性区域的完全靶向药物具有10%的相对结合亲和力。这种相对结合亲和力是令人鼓舞的，因为与类固醇Metribolone结合的人雄激素受体配体结合结构域的共晶结构预测了将内部的抗雄激素连接到外部的细胞毒素的系链的空间非常有限。
The synthesis and preliminary evaluation of a doxorubicin-formaldehyde conjugate tethered to the nonsteroidal antiandrogen, cyanonilutamide (RU 56279), for the treatment of prostate cancer are reported. The relative ability of the targeting group to bind to the human androgen receptor was studied as a function of tether. The tether served to attach the antiandrogen to the doxorubicin-formaldehyde conjugate via an N-Mannich base of a salicylamide derivative. The salicylamide was selected to serve as a trigger release mechanism to separate the doxorubicin-formaldehyde conjugate from the targeting group after it has bound to the androgen receptor. The remaining part of the tether consisted of a linear group that spanned from the 5-position of the salicylamide to the X-position of cyanonilutamide. The structures explored for the linear region of the tether were derivatives of di(ethylene glycol), tri(ethylene glycol), N,N'-disubstituted-piperazine, and 2-butyne-1,4-diol. Relative binding affinity of the tethers bound to the targeting group for human androgen receptor were measured using a 3 H-Mibolerone competition assay and varied from 18% of nilutamide binding for the butynediol-based linear region to less than 1% for one of the piperazine derivatives. The complete targeted drug with the butynediol-based linear region has a relative binding affinity of 10%. This relative binding affinity is encouraging in light of the cocrystal structure of human androgen receptor ligand binding domain bound to the steroid Metribolone which predicts very limited space for a tether connecting the antiandrogen on the inside to the cytotoxin on the outside.