From the metal ions and metal compounds that are known to bind to DNA, many anticancer Pt(II) and Ru(II)/Ru(III) compounds are known to have ligand-exchange kinetics in the same order of magnitude as the division of tumor cells. The present article discusses this process in detail with special attention to cisplatin and related compounds and the cellular binding sites and processes of such compounds. Detailed platinated DNA structures are presented and discussed in light of the mechanistic studies of metal antitumor compounds. It is now known that platinum antitumor drugs eventually end up on the DNA. However, it remains a challenge to understand how (fast) they reach the DNA and how they are removed. The kinetics of ligand exchange around platinum appear to play a crucial role, and the possible role of other ligands as intermediates, especially those with S-donor sites, is of great interest. New types of Pt compounds with additional functionalities influencing DNA binding and kinetics are discussed in the context of steric and H-bonding properties. A comparison is made with more sterically crowded Ru complexes. The effects on activity and correlations with structural and kinetic properties are clues in understanding the biological activities of these classes of compounds.

https://www.pnas.org/content/pnas/100/7/3611.full.pdf

New clues for platinum antitumor chemistry: Kinetically controlled metal binding to DNA

Since the publication of our previous Perspective dealing with polyamine drug discovery,1 the field has undergone numerous changes. Most prominent among these changes, from a medicinal chemistry point of view, is that polyamine drug discovery efforts have partially shifted away from an emphasis on inhibitors of polyamine biosynthetic and catabolic enzymes. This shift is in part due to the fact that multiple compensatory mechanisms are available that are able to maintain homeostasis in cellular polyamine pools,2 and thus the utility of specific enzyme inhibitors as drugs is limited. Specific inhibitors are available for every enzyme in the polyamine biosynthetic pathway,1, 3-6 and for the polyamine transport system.7-9 Although these inhibitors have significant effects on their respective target enzymes, only one inhibitor, α-difluoromethylornithine (DFMO) has reached the market. DFMO was originally designed as an antitumor agent, but the drug was not effective enough to warrant continued Phase II trials. However, it has been shown to be an effective cure for infection caused by Trypanosoma brucei gambiense (West African Sleeping Sickness),10, 11 and has recently shown considerable potential as a cancer chemopreventive agent (see below).12-14 Although no other polyamine biosynthesis inhibitor has been advanced to the market, the ubiquitous nature of the natural polyamines would lead one to conclude that these molecules have numerous cellular effector sites that are frequently dysregulated in cancer, and as such should provide a target rich environment for therapeutic intervention. Recent medicinal chemistry efforts in the polyamine field have focused on the discovery of compounds that produce cellular effects that are either independent of, or in addition to the polyamine metabolic enzymes. In addition, polyamine chains have been used to make hybrid drug molecules in order to improve cellular import, increase affinity for chromatin or to serve as carriers. This Perspective will focus on developments in polyamine drug discovery since our previous article.1

/pdf/recent-advances-in-the-development-of-polyamine-analogues-as-4n1gjwelxl.pdf

Recent Advances in the Development of Polyamine Analogues as Antitumor Agents

We report here the first synthesis of mesoscopic, monodisperse particles which contain nanoscopic inclusions of ferromagnetic cobalt ferrites. These monodisperse ferromagnetic composite particles readily self-assemble into magnetically responsive photonic crystals that efficiently Bragg diffract incident light. Magnetic fields can be used to control the photonic crystal orientation and, thus, the diffracted wavelength. We demonstrate the use of these ferromagnetic particles to fabricate magneto-optical diffracting fluids and magnetically switchable diffracting mirrors.

/pdf/mesoscopic-monodisperse-ferromagnetic-colloids-enable-tvhknwiep6.pdf

Mesoscopic monodisperse ferromagnetic colloids enable magnetically controlled photonic crystals.

In the series Rh2(O2CR)4 (R=CH3, 1; R=CF3, 2), [Rh2(O2CR)2(phen)2]2+ (R=CH3, 3; R=CF3, 4), and [Rh2(O2CR)2(dppz)2]2+ (R=CH3, 5; R=CF3, 6), 2, 4, and 6 are twice as cytotoxic as 1, 3, and 5, respectively. The substitution reactions of 2 with 9-ethylguanine at various temperatures take place at faster rates than those of 1, and the activation energy Ea(1)=69+/-4 kJ/mol is twice Ea(2)=35+/-2 kJ/mol. The higher cytotoxicities of [Rh2(micro-O2CCH3)2(eta1-O2CCH3)L(MeOH)]+ (L=dppz, 7; L=dppn, 8) relative to [Rh2(micro-O2CCH3)2(bpy)L]2+ (L=dppz, 10; L=dppn, 11) are attributed to the labile equatorial groups in 7 and 8 not present in 10 and 11. The toxicities of complexes 1-8 are not related to their charge or the ease by which they transverse the cellular membrane but to the lability of the ligands on the dirhodium core.

Dirhodium(II,II) complexes: molecular characteristics that affect in vitro activity.

Reactions of Mo2(O2CCH3)(DAniF)3, DAniF = N,N‘-di-p-anisylformamidinate, with oxamidate dianions [ArNC(O)C(O)NAr]2-, Ar = C6H5 and p-anisyl, give pairs of isomeric compounds where the [Mo2] units are bridged by the oxamidate anions. For the α isomers, the C−C unit of the dianion is nearly perpendicular to the Mo−Mo bonds, and these are essentially perpendicular to each other. For the β isomers, the corresponding C−C unit and the Mo−Mo bonds are essentially parallel to each other. Each type of isomer is stable in solution. The electronic communication as measured by the ΔE1/2 for the oxidation of each of the Mo2 units is significantly better for the β isomers. This is supported also by the appearance of what is conventionally called an intervalence charge-transfer band in the near infrared region upon oxidation of the β isomers but not the α isomers. Molecular mechanics and DFT calculations help explain the relative conformations in the α isomers and the relative energy differences between the α and β isomers.

/pdf/modifying-electronic-communication-in-dimolybdenum-units-by-4rxn8qjqxg.pdf

Modifying electronic communication in dimolybdenum units by linkage isomers of bridged oxamidate dianions.

Dirhodium tetraacetate is an antitumor active compound that is known to inhibit cellular DNA synthesis, but relatively little is known about its interactions with nucleic acids. A combination of ma...

Evidence for Binding of Dirhodium Bis-Acetate Units to Adjacent GG and AA Sites on Single-Stranded DNA

The synthesis and characterization of products from reactions of Rh2(form)2(O2CCF3)2(CH3CN)2 (form = N,N‘-p-ditolylformamidinate, N,N‘-diphenylformamidinate) and the partially solvated [Rh2(DTolF)2(CH3CN)6][BF4]2 (DtolF = N,N‘-p-ditolylformamidinate) with the DNA purine analogues, 9-ethylguanine, and 9-ethyladenine are described. X-ray crystallography was used to characterize Rh2(DTolF)2(O2CCF3)2(CH3CN)2 (1) which crystallizes in the space group P21/n with a = 10.849 (3) A, b = 21.435 (6) A, c = 18.677 (3) A, V = 4340 A3, Z = 4, R = 0.0451, and Rw = 0.0904. The two rhodium centers are bridged by four O2CCF3- ligands with a Rh−Rh distance of 2.24743(5) A. Compound 1 reacts with 9-ethylguanine to form Rh2(DTolF)2(9-EtGH)2(O2CCF3)2 (3) which exists as two isomers, namely head-to-head and head-to-tail as confirmed by 1H NMR spectroscopy. [Rh2(DTolF)2(CH3CN)6][BF4]2 (5) crystallizes in the Pbca space group with a = 21.646 (3) A, b = 31.272 (3) A, c = 14.561(4) A, V = 9857 A3, Z = 8, R = 0.046, and Rw = 0.063. ...

Reactions of dna purines with dirhodium formamidinate compounds that display antitumor behavior

The reaction of Rh2(OAc)4(bpy)
(bpy = 2,2′-bipyridine) with 9-ethylguanine (9-EtGH) proceeds with substitution of two acetate ligands to produce [Rh2(OAc)2(bpy)(9-EtGH)(H2O)2(CH3SO4)][CH3SO4]·(H2O)
(1), which has been structurally characterized. In compound 1, the equatorial sites of one rhodium center are occupied by a chelating bpy molecule and 9-EtGH is equatorially coordinated via N(7) to the other rhodium center. The interaction of the 9-EtGH base with the dirhodium core is further stabilized by an intramolecular hydrogen bond between the purine O(6) and the equatorial water molecule. The eight non-equivalent bpy proton resonances, as well as that of the purine H(8) (which shifts upfield upon coordination as compared to free 9-EtGH, due to bpy ring current effects), were assigned by means of 2D NMR spectroscopy. The pH titration curve of the H(8) proton reveals pH-independent behavior and a pKa value of 8.0 for N1–H deprotonation; both observations corroborate N(7) binding of the purine base to the dirhodium unit in solution. These findings indicate that, in the presence of a chelating agent that blocks one rhodium center, 9-EtGH binds to a single rhodium center in a monodentate fashion via N(7), instead of in a bridging fashion through the N(7) and O(6) sites as previously noted.

Structural evidence for monodentate binding of guanine to the dirhodium(II,II) core in a manner akin to that of cisplatin

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Evidence for Binding of Dirhodium Bis-Acetate Units to Adjacent GG and AA Sites on Single-Stranded DNA

Reactions of dna purines with dirhodium formamidinate compounds that display antitumor behavior

Structural evidence for monodentate binding of guanine to the dirhodium(II,II) core in a manner akin to that of cisplatin