Muccio D D, Brouillette W J, Breitman T R, Taimi M, Emanuel P D, Zhang X, Chen G, Sani B P, Venepally P, Reddy L, Alam M, Simpson-Herren L, Hill D L
Department of Chemistry, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
J Med Chem. 1998 May 7;41(10):1679-87. doi: 10.1021/jm970635h.
We recently synthesized several conformationally constrained retinoic acid (RA) analogues [8-(2'-cyclohexen-1'-ylidene)-3, 7-dimethyl-2,4,6-octatrienoic acids with different alkyl substituents at 2' (R1) and 3' (R2) positions on the cyclohexene ring] (Muccio et al. J. Med. Chem. 1996, 39, 3625) as cancer chemopreventive agents. UAB8 (R1 = Et; R2 = iPr), which contains sufficient steric bulk at the terminal end of the polyene chain to mimic the trimethylcyclohexenyl ring of RA, displayed biological properties similar to those of RA. To explore the efficacy of this retinoid in acute promyelocytic leukemia (APL) and juvenile myelomonocytic leukemia (JMML), we evaluated UAB8 isomers in in vitro assays which measure the capacity of retinoids to inhibit aberrant myeloid colony growth from blood or bone marrow cells obtained from human JMML patients and in assays measuring the potential of retinoids to differentiate NB4 cells (an APL cell line). Both (all-E)- and (13Z)-UAB8 were 2-fold more active than RA in the NB4 cell differentiation assay; however, only (all-E)-UAB8 had comparable activity to the natural retinoids in the JMML cell assays. These results were compared to the biological effectiveness of a new retinoid, UAB30 [8-(3', 4'-dihydro-1'(2'H)-naphthalen-1'-ylidene)-3,7-dimethyl-2,4, 6-octatrienoic acid], which had different nuclear receptor binding and transactivational properties than UAB8. Relative to (all-E)-RA and (all-E)-UAB8, (all-E)-UAB30 bound well to RARalpha but did not activate transcription-mediated RARalpha homodimers, even though it was effective in RARbeta- and RARgamma-mediated transactivational assays. In APL assays, this retinoid had much reduced activity and was only moderately effective in JMML assays and in cancer chemoprevention assays.
我们最近合成了几种构象受限的视黄酸（RA）类似物[8-(2'-环己烯-1'-亚基)-3,7-二甲基-2,4,6-辛三烯酸，在环己烯环的2'（R1）和3'（R2）位置带有不同的烷基取代基]（Muccio等人，《药物化学杂志》，1996年，39卷，3625页）作为癌症化学预防剂。UAB8（R1 = 乙基；R2 = 异丙基），在多烯链末端具有足够的空间位阻以模拟RA的三甲基环己烯基环，表现出与RA相似的生物学特性。为了探究这种类视黄醇在急性早幼粒细胞白血病（APL）和青少年粒单核细胞白血病（JMML）中的疗效，我们在体外试验中评估了UAB8异构体，这些试验用于测量类视黄醇抑制从人类JMML患者血液或骨髓细胞中异常髓系集落生长的能力，以及测量类视黄醇使NB4细胞（一种APL细胞系）分化的潜力。在NB4细胞分化试验中，(全-E)-和(13Z)-UAB8的活性均比RA高2倍；然而，在JMML细胞试验中，只有(全-E)-UAB8具有与天然类视黄醇相当的活性。这些结果与一种新的类视黄醇UAB30[8-(3',4'-二氢-1'(2'H)-萘-1'-亚基)-3,7-二甲基-2,4,6-辛三烯酸]的生物学有效性进行了比较，UAB30具有与UAB8不同的核受体结合和反式激活特性。相对于(全-E)-RA和(全-E)-UAB8，(全-E)-UAB30与RARα结合良好，但不激活转录介导的RARα同源二聚体，尽管它在RARβ和RARγ介导的反式激活试验中有效。在APL试验中，这种类视黄醇的活性大大降低，在JMML试验和癌症化学预防试验中仅具有中等效果。
