complexes. The design of platinum(IV) complexes yielded a new concept in platinum anticancer therapy. These compounds with lipophilic groups at axial positions would facilitate intestinal absorption of the drug, making oral administration possible.58 Moreover they would act as pro-drugs, which get reduced to platinum(II) by intracellular glutathione, ascorbic acid or other reducing agents. The platinum(II) would bind subsequently to DNA and exert the desired action.59, 60 The most successful Pt(IV) complex is bis(acetato)- amminedichlorido(cyclohexylamine)platinum(IV) (see Fig.1.6), also known as satraplatin or JM216. Phase II trials of this drug have been completed by GPC-Biotech in hormone- refractory prostate cancer (HRPC), ovarian cancer and small cell lung cancer.61 Phase III evaluation of satraplatin combined with prednisone is ongoing as a second-line chemotherapy treatment for patients with HRPC. Other trials evaluating the effects of satraplatin in combination with radiation therapy, in combination with other cancer therapies and in various other cancers are underway or planned.61 Satraplatin also shows in vivo oral antitumour activity against a variety of murine and human subcutaneous tumour models, comparable to the activity of cisplatin. In addition, it has a relatively mild toxicity profile, being myelosuppression instead of nephrotoxicity the dose- limiting factor.62 Sterically hindered cis-platinum(II) complexes
complexes. Since transplatin displays no antitumour activity, one of the early conclusions drawn in the SAR´s was that the cis- geometry was an essential requisite. On the other hand a complex that reacts exactly like cisplatin will never overcome resistance to it. In the search for complexes that followed a different mechanism to cisplatin the first SAR-rule was revised. Indeed a series of active trans-Pt(II) compounds was found.68 The trans-Pt(II) complexes that have been synthesised so far can be divided into several groups that respond to the general formula trans-[PtCl2(L)(L’)]. The pioneers were Xxxxxxx and his group, with complexes where L = a pyridine-like ligand and L´= an ammine, a sulfoxide or a pyridine-like group.69-72 Following his example, other groups synthesised more trans-Pt(II) complexes, finding in some cases very good anticancer activities. Xxxxxxx-Xxxxxxxxx and her group focused on complexes with L = L´ = branched aliphatic amines.73, 74 Xxxxxx and others reported that the replacement of one of transplatin´s ammine ligands by a heterocyclic ligand, such as piperidine, piperazine or 4-picoline, resulted in a radical enhancement of the cytotoxicity.75, 76 Finally the group of Natile and Coluccia synthesised complexes where L = an iminoether ligand and L´ = an amine or one more iminoether ligands.77, 78 All these groups have reported that the cytotoxic ability of the above-described trans- platinum complexes with bulky non-leaving groups is in some cases superior to that shown by cisplatin, and often better than the cytotoxicity of their respective cis- analogues. These trans- complexes are characterized by a spectrum of activity different from cisplatin and they often overcome resistance. The background concept for designing these complexes is that sterically crowded carrier ligands slow down the reaction between the platinum centre and the biomolecules.68 In addition, these complexes will cause different DNA alterations from those generated by cis-platinum complexes.71, 79 Finally, the cellular response towards these trans complexes is expected to be different than the response towards the cisplatin analogues.80 This is a mechanistically crucial point, which requires further investigation from a molecular pharmacology point of view.80, 81 Polynuclear platinum drugs In the search for platinum complexes that interact with DNA in a drastically different way to cisplatin, several dinuclear compounds were studied.82 This new approach allowed many vari...
complexes. The trinuclear platinum(II) complex 1,0,1/t,t,t or BBR3464 (see Fig.1.10) was selected for phase II trials once promising pre-clinical data had been obtained.87 BBR3464, which provides long-range intrastrand crosslink upon DNA, was found to be very potent as a cytotoxic agent, besides being effective against cisplatin-resistant tumour cells. Notable features are the potency, the ten-fold lower maximum tolerated dose (MTD) in comparison to cisplatin and the broad spectrum of tumours sensitive to this agent. Importantly, BBR3464 also displays high antitumour activity in human tumour xenografts characterized as mutant p53, tumours that are known to be insensitive to drug intervention. X0X XX0 Xx (XX0)0 X0X XX0 Xx
complexes. This property makes them the first choice in the search for compounds that display similar biological effects to platinum(II) drugs.90, 91 Very few metal drugs reach the biological target without being modified, which makes ligand exchange an important determinant of biological activity. Most metallodrugs undergo interactions with macromolecules such as proteins, or with small S-donor compounds, or even with water. Some interactions are essential for inducing the desired therapeutic properties of the complexes. As the rate of ligand exchange is dependent on the concentration of the exchanging ligands in the surrounding solution, diseases that alter these concentrations in cells or in the surrounding tissues may have an effect on the activity of the drug. The range of accessible oxidation states of ruthenium under physiological conditions makes this metal unique amongst the platinum group. The ruthenium centre, predominantly octahedral, can be Ru(II), Ru(III) or Ru(IV). Ru(III) complexes tend to be more biologically inert than related Ru(II) and Ru(IV) complexes. The redox potential of a metal complex can be modified by varying the ligands. In biological systems glutathione, ascorbate and single-electron-transfer proteins, like those involved in the mitochondrial electron-transfer chain, are able to reduce Ru(III) and Ru(IV),92 always depending on the nature of the ligands, while molecular dioxygen and cytochrome oxidase can oxidize Ru(II) in certain complexes.93-95 The redox potential of ruthenium compounds can be exploited to improve the effectiveness of Ru-based drugs in the clinic.90, 91 In many cases the altered metabolism associated with cancer and microbial infection results in lower oxygen concentration (hypoxia) in these tissues in comparison to healthy ones.96 In a healthy cell the reduction of Ru(III) to Ru(II) by glutathione is a very slow process. Besides, the Ru(II) product is readily oxidized back to Ru(III) by the dioxygen that is present in the tissue. However, the reduction of relatively inert Ru(III) complexes by glutathione is more important in the hypoxic environment of solid tumours.97 The reduction of Ru(III) to Ru(II) can be catalysed by mitochondrial and microsomal single-electron-transfer proteins, amongst others. The mitochondrial proteins are of particular interest in drug design, as they can initiate apoptosis.90 One more property of ruthenium that makes it very appreciated in medicinal chemistry is its tendency to selectively b...
complexes. We have previously reported the physical model for the xxx-xxxxx-xxxxxxxxx xxxxxxx, Xx(XX)(xxx)0(XX0)0, and found excellent agreement of this model with the X- ray crystallographic structure. Figure 4.3.5.1.B shows the superposition of the superhyperfine principal axis system for Cu(II)(him)2(NO3)2 onto the atomic coordinates of the X-ray structure for Cu(II)(him)2(NO3)2,137 in the manner of Figure 4.3.5.1.A, by using the superhyperfine principal axis systemmolecular principal axis system relation derived from the single crystal ESEEM studies.134-135 The calculated model displays excellent agreement with the ESEEM-derived model. In the case of the bis-trans- imidazole complex, the deviations between the two models are within the angular range of the confidence intervals for the Euler angles at the 0.99 confidence level. This is expected for the superhyperfine principal axis system orientations in the crystal and frozen glassy solution, because rotation of the imidazole rings about the Cu(II)-ligand axis is constrained by the bidentate coordination in the Cu(II)(him)2 complex. The reasonable agreement (within the limits expected for crystal versus glassy frozen solvent conditions) of the powder ESEEM-derived physical models for the mutual orientation of the imidazole remote 14N principal axis system with the mutual orientation calculated from the combined single crystal ESEEM and X-ray crystallographic results demonstrates that the powder 14N ESEEM experiment and numerical simulation approach, based on analysis of the 2dq line shape, is capable of accurately specifying the mutual orientation, to within the confidence intervals of the angular parameters. In contrast, in the general case of a Cu(II)-bis-Im complex of unknown structure and unknown relation of the superhyperfine principal axis system to the imidazole molecular principal axis system, the cis- or trans- coordination mode cannot be uniquely determined. The finding of a rotation matrix with no eigenvalue of -1 does, however, introduce the constraint that the mode is not trans. For example, if the two superhyperfine principal axis system of the two imidazoles in a bis-trans configuration are related by a rotational matrix R, then there must exist a vector v, corresponding to the bonding direction of the proximal 14N and Cu(II), such that, when rotated by R, becomes –v. The relationship, Rv=-v, requires R to have an eigenvalue of -1, corresponding to a 180° rotation about some reference axis. Howev...
complexes. Where a complex has been noted in a Site Plan, the Standards Unit(s) will be managed according to the dominant site series as identified in the Site Plan.
complexes. For students designed as “Special Handling,” the bus driver or aide may be required to provide assistance to and from the pick-up and drop-off location. Contractor may request an adjustment in price if an aide is required. All physically handicapped riders who are in wheelchairs will be required to have an operable seatbelt on the wheelchair. Contractor shall notify the student’s school immediately if the bus driver determines that the student’s wheelchair has a safety- related defect that would prevent the student from being transported safely. Any rider whose wheelchair is determined to have a safety related defect will not be transported until such defect is repaired. MPS reserves the right to add other students to this contract as deemed appropriate. Students are to be picked up and dropped off at their residence, baby-sitter, or day care. Students may be picked up and dropped off at different locations. The “Absence of Responsible Person” policy applies to all riders in this program. Contractor recognizes that OI students are placed in schools throughout the school year, with the largest influx within the first three months of the school year. MPS will provide an initial set of routes prior to the start of the school year. After that date, MPS will process all updates and notice of changes will be sent to contractor. Contractor will be responsible for notifying schools and parents of the change. Contractor may change routes to service riders in the most efficient manner possible. MPS will review and approve all routes. Other route changes may be provided by MPS Pupil Transportation. Contractor shall be required to demonstrate that drivers assigned to these routes have successfully completed a training program on transporting students with special needs. MPS Pupil Transportation will review the training program for completeness. Contractor may elect to use MPS Division of Special Education staff to conduct a training program. Cost and availability for this service will be negotiated with MPS Division of Special Education Services. Contractor is responsible for providing, at its own expense, all personnel and materials required to perform the services under this Contract.
