Novel Oximato-Bridged Platinum(II) Di- and Trimer(s): Synthetic, Structural, and in Vitro Anticancer Activity Studies

Novel platinum complexes of trans geometry [PtCl2{(Z)-R(H)CNOH}2] [R = Me (1), Et (3)] and [PtCl2{(E)-R(H)CNOH}{(Z)-R(H)CNOH}] [R =
Me (2), Et (4)] as well as the classic trans-[PtCl2(R2CNOH)2] [R = Me, Et] were reacted with an equivalent amount of silver acetate
in acetone solution at ambient temperature, resulting in formation
of unprecedented head-to-tail-oriented oximato-bridged dimers [PtCl{μ-(Z)-R(H)CNO}{(Z)-R(H)CNOH}]2 [R = Me (5), Et (7)], [PtCl{μ-(Z)-R(H)CNO}{(E)-R(H)CNOH}]2 [R = Me (6), Et (8)], and [PtCl(μ-R2CNO)(R2CNOH)]2 [R =
Me (9), Et (10)], correspondingly. The
dimeric species feature a unique six-membered diplatinacycle and represent
the first example of oxime ligands coordinated to platinum via the
oxygen atom. All complexes were characterized by elemental analyses,
electrospray ionization mass spectrometry, IR and multinuclear (1H, 13C, and 195Pt) NMR spectroscopy,
as well as X-ray diffraction in the cases of dimers 6 and 9. Furthermore, the crystal and molecular structures
of a trimeric oximato-bridged complex 11 comprising three
platinum units connected in a chain way were established. The cytotoxicity
of both dimers and the respective monomers was comparatively evaluated
in three human cancer cell lines: cisplatin-sensitive CH1 cells as
well as cisplatin-resistant SW480 and A549 cells, whereupon structure–activity
relationships were drawn. Thus, it was found that dimerization results
in a substantial (up to 7-fold) improvement of IC50 values
of (aldoxime)PtII compounds, whereas for the analogous
complexes featuring ketoxime ligands the reverse trend was observed.
Remarkably, the novel dimers yielded no cross-resistance with cisplatin
in SW480 cells, exhibiting up to 2-fold enhanced cytotoxicity in
comparison with the CH1 cell line and thereby possessing a promising
potential to overcome resistance toward platinum anticancer drugs.
The latter point was also confirmed by investigating the potency of
apoptosis induction in the case of one monomer as well as one dimer;
the investigated complexes proved to be strong apoptotic agents which
could induce cell death even in the cisplatin-resistant SW480 cell
line.

一系列具有反式构型（trans geometry）的新型铂配合物：反式-[PtCl₂{(Z)-R(H)C=NOH}₂] [R = 甲基（1）、乙基（3）]，以及反式-[PtCl₂{(Z)-R(H)C=NOH}{(E)-R(H)C=NOH}] [R = 甲基（2）、乙基（4）]，另有经典的反式-[PtCl₂(R₂C=NOH)₂] [R = 甲基、乙基]，于室温丙酮溶液中与等当量乙酸银反应，最终生成前所未有的头对尾取向肟桥联二聚体（oximato-bridged dimers）：[PtCl{μ-(Z)-R(H)C=NO}{(Z)-R(H)C=NOH}]₂ [R = 甲基（5）、乙基（7）]、[PtCl{μ-(Z)-R(H)C=NO}{(E)-R(H)C=NOH}]₂ [R = 甲基（6）、乙基（8）]与[PtCl(μ-R₂C=NO)(R₂C=NOH)]₂ [R = 甲基（9）、乙基（10）]，产物与反应物一一对应。该二聚体物种具有独特的六元双铂环（diplatinacycle），是首例通过氧原子与铂配位的肟配体配合物。所有配合物均通过元素分析、电喷雾电离质谱（electrospray ionization mass spectrometry）、红外光谱（IR）以及多核核磁共振波谱（¹H、¹³C和¹⁹⁵Pt NMR）完成表征，其中二聚体6与9还通过X射线衍射（X-ray diffraction）确定了晶体结构。此外，本研究还解析了由三个铂单元以链状方式连接的肟桥联三聚体配合物11的晶体与分子结构。本研究对所合成的二聚体与对应单体在三种人类癌细胞系中开展了细胞毒性对比评价：顺铂（cisplatin）敏感的CH1细胞，以及顺铂耐药的SW480与A549细胞，并据此构建了构效关系（structure–activity relationships）。研究发现，二聚化可使（醛肟）Pt(II)配合物的IC₅₀值显著提升（最高达7倍），而带有酮肟配体的类似配合物则呈现相反趋势。值得注意的是，新型二聚体在SW480细胞中未表现出与顺铂的交叉耐药性，且相较于CH1细胞系，其细胞毒性最高提升2倍，因此具备克服铂类抗肿瘤药物耐药性的良好应用潜力。这一结论也通过对一种单体与一种二聚体的凋亡（apoptosis）诱导活性研究得到验证：所测试的配合物均为强效凋亡诱导剂，即便在顺铂耐药的SW480细胞系中也可诱导细胞死亡。