Naslov
New Mn porphyrins for stroke therapy

Autori
Tovmasyan, Artak ; Rajić, Zrinka ; Spasojević, Ivan ; Sheng, Huaxin ; Warner, David S. ; Batinić-Haberle, Ines

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
6th International Conference on Porphyrins and Phthalocyanines, ICPP-6 / - , 2010, 478-478

Skup
6th International Conference on Porphyrins and Phthalocyanines, ICPP-6

Mjesto i datum
Albuquerque (NM), Sjedinjene Američke Države, 04.07.2010. - 09.07.2010

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
Mn porphyrins; stroke

Sažetak
Oxidative stress and reactive oxygen and nitrogen species are involved in central nervous system injuries, such as stroke, spinal cord injury, cerebral palsy, chronic morphine tolerance, hemorrhage etc. Besides primary oxidative stress as a consequence of ischemia and reperfusion, the subsequent upregulation of cellular transcriptional activity leads to excessive inflammation and eventually to irreparable damage. Potent catalytic antioxidants, Mn(III) N-alkylpyridylporphyrins, in particular the lipophilic hexyl analogue MnTnHex-2-PyP5+, are able to significantly decrease stroke infarct size and neurologic deficit, even if given with clinically relevant delays after reperfusion in a 90-min middle cerebral artery occlusion model. Effects are due to their ability to eliminate superoxide [log kcat(O2 .-)] and peroxynitrite [log k(ONOO-)], thereby suppressing redox-based pro-inflammatory transcriptional activity. Due to its lipophilicity, MnTnHex-2-PyP5+ is efficacious even if given intravenously, and at only 0.45 mg/kg/day. Any modification of alkyl or substituted alkyl pyridyl chains, whereby charges (thus thermodynamics, E1/2 and kinetics for O2 .- dismutation and peroxynitrite reduction) are maintained on the pyridyl nitrogens, has essentially no impact on kcat but affects lipophilicity and/or toxicity. Herein we report efforts on the synthesis of new methoxyhexyl analogue, MnTMOHex-2(3, 4)-PyP5+ (shown below). We have already reported that if one carbon atom in the alkyl chain of butylpyridylporphyrin (MnTnBu-2-PyP5+) is replaced with oxygen, the micellar-based toxicity drops remarkably ; the lipophilicity (POW) of such methoxyethylpyridylporphyrin (MnTMOE-2-PyP5+), while lower than of butyl, was still somewhat higher than of ethyl porphyrin. Thus, if we apply the same strategy to an octyl analogue, we would maintain the lipophilicity of hexyl (critical for crossing the blood brain barrier), but decrease toxicity. In turn, such modification would allow us to increase the dosing of MnTMOHex-2-PyP5+ which in turn would enhance therapeutic stroke efficacy. Here we tabulate the parameters of known and new Mn porphyrins that are relevant for their efficacy in stroke. (Grants: U19AI067798, Duke University’s CTSA grant 1 UL 1 RR024128-01 from NCRR/NIH).

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Kliničke medicinske znanosti

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