The lengths of the alkyl chain were ranged from 7.7~11.5 Å, while the rise of three layers of G-tetrads was around 10 Å. Silver nitrate was first used to remove one chloride from Pt(Dip)Cl 2 which enabled alkyl diamine to connect two Pt centres via coordination of amine. Pt(Dip)Cl 2 was prepared as literature 25. Alkyl linkages with seven to ten methylene groups were used to optimize the distances between two complex components for simultaneous non-covalent and covalent interactions with GQ structures.ĭesign and synthesis of the dinuclear platinum complexesĭinuclear platinum complex Pt1 to Pt4 were synthesized as Scheme S1. 1A) with the following properties: (1) each Pt(II) coordinated to a Dip ligand in order to offer π-π stacking on G-tetrads (2) One chloride was chelated to each Pt(II) and acted as a leaving group to enable the cross-linking reaction to the purine bases in GQ sequences, such as guanine (3) An alkyl diamine filled the last coordination site to link two components.
![g force platinum g force platinum](https://www.grupobaruch.com/images/product/619/og-g-force-gb-16-203813.jpg)
G force platinum series#
In order to achieve the dual stabilization and cross-linking functions, we designed and synthesized a series of dinuclear Pt-Dip compounds (Fig. 1), which can efficiently stabilize GQ with aromatic stacking of phenanthroline ligands and further possess high binding preference towards parallel c-myc GQ via four phenyl groups docking into the lateral grooves 25. Our group has recently reported a platinum compound, (PF 6) 2 ( Pt0, Dip: 4,7-diphenyl-1,10-phenanthroline, Fig. Whereas, dinuclear metal complex possessed unique binding module on GQ and is a good means to offer a novel approach to form dual functions of both long-range cross-linking and stabilization on G-tetrads. Further modification of Pt-tolylterpyridine complex by classical photo-crosslinking groups-benzophenone and tetraphenylazide can achieved improved selectivity to different GQ sequences, with the formation of a second covalent bond between Pt-ttpy-N 3 and GQ upon photoactivation 24. Teulade-Fichou group showed a set of mononuclear Pt-terpyridine complexes could exclusively coordinate to the loop adenine, meanwhile, with an enhanced binding affinity and platinating activity after extending the aromatic surface of the terpyridine moiety 23.
![g force platinum g force platinum](https://live.staticflickr.com/6013/5935436524_74583161dc_n.jpg)
A couple of organic molecules as GQ stabilizer were conjugated with monochloro-platinum complexes to achieve a dual noncovalent/covalent interaction with telomeric GQ 21, 22. Though small molecules as both GQ stabilizer and cross-linking agents could be more promising in anticancer potency, the studies of these dual functional drug candidates are significantly inadequate. Bombard and co-workers demonstrated the cross-linking between human telomere sequence and cis-/transplatin, with several binding sites including adenines in the loop region and guanines in the external G-quartet 20.
![g force platinum g force platinum](http://2.bp.blogspot.com/_By0_FtFTtkI/TUJcwWo_WXI/AAAAAAAAASg/enNS9eN2e7M/s1600/ripsfedonthewaybacktoge+%252818%2529.jpg)
For example, cisplatin formed an intra-strand adduct on telomere sequences, which inhibited telomerase activity and, eventually induced telomere loss and tumour cell death 18, 19. Pt-DNA adducts could interfere the recognition/binding of protein factors and the downstream biological pathways to exert the anticancer therapeutic effects. Beyond non-covalent interactions with DNA, Pt(II) complexes can covalently cross-link to the purines. Among these binders, dinuclear metal complexes, due to the unique cooperative bindings of two complex components, achieved excellent selectivity for GQ structures and the reduced drug tolerance of tumour cells comparing to mononuclear metal complexes as anticancer drug candidates 15, 16, 17. So far, substantial amount of organic compounds and metal complexes have been reported with excellent stabilization on GQ mainly via π-π stacking with G-tetrads and lead to potent antitumor activity 11, 12, 13, 14. The significant biological roles of GQ attracted great interests to design GQ-targeting molecules for cancer therapy. The formation of G-quadruplexes was proposed to either regulate the oncogene expression or inhibit the telomerase activity 8, 9, 10. GQ was folded by the G-rich sequences from human telomeres that located at the terminal of chromosomes, as well as the promotor regions of many oncogenes, such as c-myc, c-kit and bcl2 5, 6, 7. Stacking of more than two layers of G-tetrads provided guanine quadruplexes (GQ) 1, 2, 3, 4.
![g force platinum g force platinum](https://ecoomm.com/wp-content/uploads/2020/11/WhatsApp-Image-2020-11-17-at-10.01.18-AM-600x495.jpeg)
Guanine-rich DNA sequences are prone to self-assemble into several layers of planar G-tetrad by Hoogsteen hydrogen bonds in the presence of cations, such as sodium and potassium ion.