Synthesis of Small-Molecule Probes of Bilirubin Photochemistry and Biology
Taufiqueahmed Mujawar a
; Petr Sevelda a
; Jakub Švenda* a, b
a
Masaryk University, Faculty of Science, Department of Chemistry, Kamenice 5/A8, 623 00 Brno,
Czech Republic
b
International Clinical Research Center, St. Anne’s University Hospital Brno, Pekařská 53, 656 91
Brno, Czech Republic
mtaufiqueahmed@sci.muni.cz; svenda@chemi.muni.cz
Yellow pigment bilirubin is the well-known primary product of heme catabolism.1
It is a
powerful antioxidant and a potent signaling molecule with multiple speculated biological functions.
When exceeding safe levels in the blood, particularly during the neonatal period, severe
hyperbilirubinemia can result and lead to neurotoxicity accounting for some instances of neonatal
morbidity and mortality.2,3
Despite the worldwide use of phototherapy and numerous scientific
studies thereof, there remain important unanswered questions about the photochemistry, the
biology, and the clinical aspects of the therapy. Bilirubin gives rise to various molecular fragments
formed through (photo)oxidative transformations.4
Standards of such bilirubin-derived products
are essential for studies of their bioactivities and mechanisms of formation in the context of
hyperbilirubinemia phototherapy. Unfortunately, accessing these in the analytically pure form is in
many cases problematic. The main objective of our work is to formulate a flexible synthetic strategy
that will deliver pure samples of bilirubin and the oxidative degradation products as analytical
standards or isotope-labeled probes. Our approach pursues a convergent and flexible strategy
featuring pre-functionalized and easily varied cyclic building blocks. Through a series of metalcatalyzed
annulations and cross-coupling reactions, we have been able to rapidly prepare subunits
of bilirubin and selected degradation products. The approach also permits late-stage 15
N labeling
of selected rings of bilirubin or fragments thereof.
Ref.:
(1) Bhagavan, N. V.; Ha, C. E. Essentials of Medical Biochemistry; Elsevier, 2015.
(2) Vitek, L.; Ostrow, J. Curr. Pharm. Des. 2009, 15, 2869–2883.
(3) Jašprová, J.; Dal Ben, M.; Hurný, D.; Hwang, S.; Žížalová, K.; Kotek, J.; Wong, R. J.;
Stevenson, D. K.; Gazzin, S.; Tiribelli, C.; Vítek, L. Sci. Rep. 2018, 8, 7444.
(4) Seidel, R. A.; Claudel, T.; Schleser, F. A.; Ojha, N. K.; Westerhausen, M.; Nietzsche, S.;
Sponholz, C.; Cuperus, F.; Coldewey, S. M.; Heinemann, S. H.; Pohnert, G.; Trauner, M.;
Bauer, M. J. Hepatol. 2017, 67 (2), 272–281.
NH HN
HNNH
H3C
HO2C CO2H
CH3
H3C
CH3
O O
Bilirubin