Chemotherapy-induced peripheral neuropathy (CIPN) accompanied by chronic neuropathic pain is a major dose-limiting side effect of a large number of antitumoral agents including paclitaxel (Taxol). We also demonstrate the prevention of CIPN with our two new orally active PNDCs, SRI6 and SRI110. The improved chemical design of SRI6 and SRI110 also affords selectivity for PN over other reactive oxygen species (such as superoxide). Our findings identify PN as a critical determinant of CIPN, while providing the rationale toward development of superoxide-sparing and "PN-targeted" therapeutics.

We report a new series of bis-cyclohexano-fused Mn(III) complexes of bis-hydroxyphenyldipyrromethenes (DIPYs) 4a-c as potent and orally active peroxynitrite scavengers. Complexes 4a-c have been shown to reduce peroxynitrite through a 2-electron mechanism thereby forming the corresponding Mn(V)O species, which have been characterized by UV, NMR, and LCMS methods. Mn(III) complex 4b and its strained BODIPY analogue 9b have been analyzed by x-ray crystallography. Finally, complex 4a has been shown to be an orally active and potent analgesic in a model carrageenan-induced hyperalgesia known to be driven by the overproduction of peroxynitrite.The overproduction of reactive oxygen species (ROS) in vivo is now widely recognized as a key contributor to numerous pathologies. 1 One particularly damaging situation results from the diffusion controlled radical coupling of the central ROS, superoxide, with nitric oxide to form peroxynitrite. 2 The highly reactive peroxynitrite is a powerful biological oxidant which leaves a trail of dysfunctional oxidized and nitrated proteins, lipids and nucleotides, in its wake. 3 From a pharmacological perspective, peroxynitrite is considered a potent proinflammatory and proapoptotic species which plays a critical role in pain of several etiologies as demonstrated initially by our team and then by others. [4][5][6] Accordingly, the discovery of pharmaceutically relevant agents which can effectively decompose peroxynitrite should have significant therapeutic value. 2,3 As a result of the early discoveries of Groves7 and Stern, 8 Mn(III) and Fe(III) porphyrins have emerged as an important class of peroxynitrite reductase and isomerase catalysts, respectively (Figure 1 A). Elegant mechanistic studies have revealed that the more pharmacologically-suitable Mn(III) porphyrins decompose peroxynitrite primarily in a oneelectron fashion and require a biological co-reductant such as ascorbate to complete the reductase catalytic cycle.9 One electron reduction of peroxynitrite produces the potentially damaging nitrogen dioxide radical which is also thought to undergo rapid reduction by Recently, Gross has reported that Mn(III) and Fe(III) corroles are also excellent peroxynitrite decomposition catalysts. 11 Remarkably, the Mn(III) corroles operate through a 2-electron cycle, reducing peroxynitrite to nitrite instead of nitrogen dioxide through a novel disproportionation mechanism. The most important finding from this work was that Mn(III) corroles can decompose peroxynitrite in a catalytic fashion (in contrast to Mn(III) porphyrins) and therefore do not require the assistance of endogenous co-reductants.Although Mn(III) porphyrins, such as Mn(III)-4-TMPyP 5+ 1, and Mn(III) corrole systems, such as compound 2, have proven to be powerful pharmacological tools in animal studies demonstrating the benefits of destroying peroxynitrite in vivo,11 -14 they are not optimal as therapeutic candidates. While these types of polycationic complexes have excellent catalytic activities and their high water so...

Redox-active metalloporphyrins represent the most well characterized class of catalysts capable of attenuating oxidative stress in vivo through the direct interception and decomposition of superoxide and peroxynitrite. While many interesting pharmacological probes have emerged from these studies, few catalysts have been developed with pharmaceutical properties in mind. Herein we describe our efforts to identify new Mn(III)-porphyrin systems with enhanced membrane solubilizing properties. To this end seven new Mn(III)-tetracyclohexenylporphyin (TCHP) analogues 7, 10, 12, 15, 16a–c have been prepared in which the beta-fused cyclohexenyl rings provide a means to shield the charged metal center from the membrane during passive transport. Compounds 7, 15, and 16a–c have been shown to be orally active and potent analgesics in a model of carrageenan-induced thermal hyperalgesia. In addition oral administration of compound 7 (10–100 mg/kg, n = 5) has been shown to dose dependently reverse mechano-allodynia in the CCI model of chronic neuropathic pain.

Treatment of severe pain by morphine, the gold-standard opioid and a potent drug in our arsenal of analgesic medications, is limited by the eventual development of hyperalgesia and analgesic tolerance. We recently reported that systemic administration of a peroxynitrite (PN) decomposition catalyst (PNDC) or superoxide dismutase mimetic attenuates morphine hyperalgesia and antinociceptive tolerance and reduces PN-mediated mitochondrial nitroxidative stress in the spinal cord. These results suggest the potential involvement of spinal PN signaling in this setting; which was examined in the present study. PN removal with intrathecal delivery of manganese porphyrin-based dual-activity superoxide/PNDCs, MnTE-2-PyP5+ and the more lipophilic MnTnHex-2-PyP5+, blocked hyperalgesia and antinociceptive tolerance in rats. Noteworthy is that intrathecal MnTnHex-2-PyP5+ prevented nitration and inactivation of mitochondrial manganese superoxide dismutase. Mitochondrial manganese superoxide dismutase inactivation enhances the superoxide-to-PN pathway by preventing the dismutation of superoxide to hydrogen peroxide, thus providing an important enzymatic source for PN formation. Additionally, intrathecal MnTnHex-2-PyP5+ attenuated neuroimmune activation by preventing the activation of nuclear factor kappa B, extracellular-signal-regulated kinase and p38 mitogen activated protein kinases, and the enhanced levels of proinflammatory cytokines, interleukin (IL)-1β and IL-6, while increasing anti-inflammatory cytokines, IL-4 and IL-10. The role of PN was further confirmed using intrathecal or oral delivery of the superoxide-sparing PNDC, SRI-110. These results suggest that mitochondrial-derived PN triggers the activation of several biochemical pathways engaged in the development of neuroinflammation in the spinal cord that are critical to morphine hyperalgesia and tolerance, further supporting the potential of targeting PN as an adjunct to opiates to maintain pain relief.

Peroxynitrite has been implicated in β-cell dysfunction and insulin resistance in obesity. Chemical catalysts that destroy peroxynitrite, therefore, may have therapeutic value for treating type 2 diabetes. To this end, we have recently demonstrated that Mn(III) bis(hydroxyphenyl)-dipyrromethene complexes, SR-135 and its analogues, can effectively catalyze the decomposition of peroxynitrite in vitro and in vivo through a 2-electron mechanism (Rausaria et al. 2011). To study the effects of SR-135 on glucose homeostasis in obesity, B6D2F1 mice were fed with a high fat-diet (HFD) for 12 weeks and treated with vehicle, SR-135 (5 mg/kg), or a control drug SRB for 2 weeks. SR-135 significantly reduced fasting blood glucose and insulin levels, and enhanced glucose tolerance as compared to HFD control, vehicle or SRB. SR-135 also enhanced glucose-stimulated insulin secretion based on ex vivo studies. Moreover, SR-135 increased insulin content, restored islet architecture, decreased islet size, and reduced tyrosine nitration and apoptosis. These results suggest that a peroxynitrite decomposing catalyst enhances β-cell function and survival under nutrient overload.

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