双核Pt(Ⅳ)配合物与Guanosine-5''''-Monophosphate和Glutathione反应的核磁共振光谱研究

合成了一个新型的双核Pt(Ⅳ)配合物{[cis-Pt(NH3)2Cl(OH)2]2(4,4'-methylenedianiline)}(NO3)2(化合物1)及相应的 15N标记化合物{[cis-Pt(15NH3)2Cl(OH)2]2(4,4'-methylenedianiline)}(NO3)2(化合物15N-1).利用1H NMR和ESMS进行了结构表征,化合物15N-1的2D[1H,15N]HSQC NMR发现,该化合物在水溶液中存在同分异构体.2D[1H,15N]HSQC NMR技术跟踪了化合物15N-1与Guanosine-5'-Monophosphate(5'-GMP)和Glutathione(GSH)的反应.结果显示,5'-GMP能在0.5 h内将化合物1还原,而GSH在6 h以后才能够部分的将化合物1还原.化合物1所表现出来的反应性能将有利于提高其治疗效果和降低毒副作用.     

A Fully Synthetic Four‐Component Antitumor Vaccine Consisting of a Mucin Glycopeptide Antigen Combined with Three Different T‐Helper‐Cell Epitopes

In a new concept of fully synthetic vaccines, the role of T‐helper cells is emphasized. Here, a synthetic antitumor vaccine consisting of a diglycosylated tumor‐associated MUC1 glycopeptide as the B‐cell epitope was covalently cross‐linked with three different T‐helper‐cell epitopes via squaric acid ligation of two linear (glyco)peptides. In mice this four‐component vaccine administered without external immune‐stimulating promoters elicit titers of MUC1‐specific antibodies that were about eight times higher than those induced by a vaccine containing only one T‐helper‐cell epitope. The promising results indicate that multiple activation of different T‐helper cells is useful for applications in which increased immunogenicity is required. In personalized medicine, in particular, this flexible construction of a vaccine can serve as a role model, for example, when T‐helper‐cell epitopes are needed that match human leukocyte antigens (HLA) in different patients.     

Organometallic Antitumor Compounds: Ferrocifens as Precursors to Quinone Methides

The synthesis and chemical oxidation profile of a new generation of ferrocifen derivatives with strong antiproliferative behavior in vitro is reported. In particular, the hydroxypropyl derivative HO(CH₂)₃C(Fc)=C(C₆H₄OH)₂ ( 3 b ) exhibited exceptional antiproliferative activity against the cancer cell lines HepG2 and MDA‐MB‐231 TNBC, with IC₅₀ values of 0.07 and 0.11 μM , respectively. Chemical oxidation of 3 b yielded an unprecedented tetrahydrofuran‐substituted quinone methide (QM) via internal cyclization of the hydroxyalkyl chain, whereas the corresponding alkyl analogue CH₃CH₂‐C(Fc)=C(C₆H₄OH)₂ merely formed a vinyl QM. The ferrocenyl group in 3 b plays a key role, not only as an intramolecular reversible redox “antenna”, but also as a stabilized carbenium ion “modulator”. The presence of the oxygen heterocycle in 3 b‐QM enhances its stability and leads to a unique chemical oxidation profile, thus revealing crucial clues for deciphering its mechanism of action in vivo.     

A Cytostatic Ruthenium(II)–Platinum(II) Bis(terpyridyl) Anticancer Complex That Blocks Entry into S Phase by Up‐regulating p27KIP1

Cytostatic agents that interfere with specific cellular components to prevent cancer cell growth offer an attractive alternative, or complement, to traditional cytotoxic chemotherapy. Here, we describe the synthesis and characterization of a new binuclear Ru^II–Pt^II complex [Ru(tpy)(tpypma)Pt(Cl)(DMSO)]³⁺ (tpy=2,2′:6′,2′′‐terpyridine and tpypma=4‐([2,2′:6′,2′′‐terpyridine]‐4′‐yl)‐N‐(pyridin‐2‐ylmethyl)aniline), VR54, which employs the extended terpyridine tpypma ligand to link the two metal centres. In cell‐free conditions, VR54 binds DNA by non‐intercalative reversible mechanisms (K_b=1.3×10⁵ M ^?1) and does not irreversibly bind guanosine. Cellular studies reveal that VR54 suppresses proliferation of A2780 ovarian cancer cells with no cross‐resistance in the A2780CIS cisplatin‐resistant cell line. Through the preparation of mononuclear Ru^II and Pt^II structural derivatives it was determined that both metal centres are required for this anti‐proliferative activity. In stark contrast to cisplatin, VR54 neither activates the DNA‐damage response network nor induces significant levels of cell death. Instead, VR54 is cytostatic and inhibits cell proliferation by up‐regulating the cyclin‐dependent kinase inhibitor p27^KIP1 and inhibiting retinoblastoma protein phosphorylation, which blocks entry into S phase and results in G1 cell cycle arrest. Thus, VR54 inhibits cancer cell growth by a gain of function at the G1 restriction point. This is the first metal‐coordination compound to demonstrate such activity.     

Core‐Scaffold‐Inspired Asymmetric Synthesis of Polysubstituted Chiral Hexahydropyridazines that Potently Inhibit Breast Cancer Cell Proliferation by Inducing Apoptosis

The highly enantioselective preparation of pharmacologically interesting hexahydropyridazine derivatives based on a multicomponent cascade reaction is described. This one‐pot approach utilizes an organocatalytic Michael reaction followed by intermolecular α‐amination and intramolecular hemiaminalization to yield a chiral pyridazine backbone with contiguous stereogenic centers and multiple functional groups in good yield and with high stereoselectivity. Compounds synthesized by this method potently inhibited proliferation of MCF‐7 breast cancer cells. Mechanistic studies suggest that compound 5 c exerts these anticancer effects by inducing apoptosis through extracellular signal related kinase (ERK)‐ and poly(adenosine diphosphate ribose) polymerase (PARP)‐regulated pathways, as well as mitochondrial pathways.