Ford J M, Prozialeck W C, Hait W N
Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06510.
Mol Pharmacol. 1989 Jan;35(1):105-15.
Phenothiazines and structurally related compounds inhibit cellular proliferation and sensitize multidrug-resistant (MDR) cells to chemotherapeutic agents. To identify more potent pharmaceuticals, we studied the structure-activity relationships of 30 phenothiazines and related compounds on cellular proliferation and MDR in sensitive MCF-7 and resistant MCF-7/DOX human breast cancer cells. Substitutions on the phenothiazine ring that increased hydrophobicity increased antiproliferative and anti-MDR activities. For example, -Cl and -CF3 groups increased whereas -OH groups decreased potency. Modifying the length of the alkyl bridge and the type of amino side chain also influenced potency. Compounds with increased activity against cellular proliferation and MDR possessed a four-carbon bridge rather than a three- or two-carbon bridge and a piperazinyl amine rather than a noncyclic amino group. Compounds with tertiary amines were better anti-MDR agents than those with secondary or primary amines but were equipotent antiproliferative agents. The effects of these substituents were unrelated to hydrophobicity. The structure-activity relationships suggest that an ideal phenothiazine structure for reversing MDR has a hydrophobic nucleus with a -CF3 ring substitution at position 2, connected by a four-carbon alkyl bridge to a para-methyl-substituted piperazinyl amine. We subsequently studied related compounds having certain of these properties. Substitution of a carbon for a nitrogen at position 10 of the tricyclic ring, with a double bond to the side chain (thioxanthene), further increased activity against MDR. For example, (trans)-flupenthixol, the most potent of these compounds, increased the potency of doxorubicin against MDR cells by 15-fold, as compared with its stereoisomer (cis)-flupenthixol (5-fold) or its phenothiazine homolog fluphenazine (3-fold). (cis)- and (trans)-flupenthixol were equipotent antiproliferative agents. (trans)-flupenthixol was not accumulated more than (cis)-flupenthixol in MDR cells, implying that their stereospecific anti-MDR effects were not the result of selective differences in the access of the drugs to intracellular targets. Both drugs increased the accumulation of doxorubicin in MDR cells, but not in sensitive cells, suggesting that they modulate MDR by interacting with a uniquely overexpressed cellular target in these resistant cells. The apparent lack of clinical toxicity of (trans)-flupenthixol makes it an attractive drug for further investigation.
吩噻嗪类及其结构相关化合物可抑制细胞增殖，并使多药耐药（MDR）细胞对化疗药物敏感。为了鉴定更有效的药物，我们研究了30种吩噻嗪类及其相关化合物对敏感的MCF-7和耐药的MCF-7/DOX人乳腺癌细胞的细胞增殖和多药耐药的构效关系。吩噻嗪环上增加疏水性的取代基可增强抗增殖和抗多药耐药活性。例如，-Cl和-CF3基团可增强活性，而-OH基团则降低活性。改变烷基桥的长度和氨基侧链的类型也会影响活性。对细胞增殖和多药耐药活性增强的化合物具有四碳桥而非三碳或二碳桥，以及哌嗪基胺而非非环状氨基。叔胺类化合物比仲胺或伯胺类化合物是更好的抗多药耐药剂，但它们的抗增殖活性相当。这些取代基的作用与疏水性无关。构效关系表明，用于逆转多药耐药的理想吩噻嗪结构具有一个疏水核，在2位有一个-CF3环取代基，通过一个四碳烷基桥连接到对甲基取代的哌嗪基胺。我们随后研究了具有这些性质中某些性质的相关化合物。在三环的10位用碳取代氮，并与侧链形成双键（噻吨），进一步增强了对多药耐药的活性。例如，这些化合物中活性最强的（反式）氟哌噻吨，与它的立体异构体（顺式）氟哌噻吨（5倍）或其吩噻嗪同系物氟奋乃静（3倍）相比，使阿霉素对多药耐药细胞的活性提高了15倍。（顺式）和（反式）氟哌噻吨的抗增殖活性相当。（反式）氟哌噻吨在多药耐药细胞中的蓄积并不比（顺式）氟哌噻吨多，这意味着它们的立体特异性抗多药耐药作用不是药物进入细胞内靶点的选择性差异的结果。两种药物都增加了阿霉素在多药耐药细胞中的蓄积，但在敏感细胞中则没有，这表明它们通过与这些耐药细胞中独特过度表达的细胞靶点相互作用来调节多药耐药。（反式）氟哌噻吨明显缺乏临床毒性，这使其成为进一步研究的有吸引力的药物。
