Abstrakt: Photoactivatable compounds, also called caged compounds, are those which, upon photoactivation, irreversibly release a species possessing desirable physical, chemical, or biological qualities. Short-wavelength UV radiation is not compatible with many biological and medical applications because it can induce adverse side-reactions. Photorelease induced by red or NIR light is most desired, as the tissue absorption is limited by the absorption of hemoglobin below 600 nm and absorption of water over 900 nm.

Only a few known photoactivatable (caged) molecules can be activated directly by visible/NIR light because the delivered excitation energy is in principle too low for a covalent bond cleavage. In the past 5 years, we have introduced several new chromophores absorbing in the region of 600-1100 nm that can release biologically relevant species,^1-3 for example, H₂S or CO as gaseous signaling molecules. The design, photoreaction mechanisms, spectroscopy and biological applications of these systems will be presented.

Literatura:
[1] Palao E., Slanina T., Muchová L., Šolomek T., Vítek L., Klán P.: J. Am. Chem. Soc. 2016, 138, 126-133.
[2] Slanina T., Shrestha P., Palao E., Kand D., Peterson J., Dutton A., Rubinstein N., Weinstain R., Winter A., Klán P.: J. Am. Chem. Soc. 2017, 139, 15168-15175.
[3] Šolomek T., Wirz J., Klán P.: Acc. Chem. Res. 2015, 48, 3064-3072.

Abstrakt: Chiral organic molecules are essential to our society so the development of efficient and selective methods to build such molecules is highly important. In this regard, enantioselective catalysis represents a powerful and industrially-relevant tool to access enantioenriched chiral compounds without using stoichiometric chiral reagents. Despite continuous advances in this field, the enantioselective conversion of simple chemicals into relevant chiral molecules remains a formidable challenge. Indeed, contemporary enantioselective methods still routinely require elaborated or pre-activated starting materials as the use of readily available but unactivated substrates often leads to poor reactivity and/or low selectivities. In this lecture, I will present the development of catalytic systems enabling a streamlined access to complex and valuable chiral molecules starting from simple and unactivated substrates.

Literatura:
[1] T. Saget, S. J. Lemouzy, N. Cramer, Angew. Chem. Int. Ed. 2012, 51, 2238.
[2] B. M. Trost, C.-I. Hung, T. Saget, E. Gnanamani, Nat. Catal. 2018, 1, 523.

Abstrakt: Natural products often embody desirable properties of bioactive molecules and have a long history in basic research and human medicine. Few drugs, however, are themselves natural products and the semisynthetic derivatives predominate. Fully synthetic approaches have the exciting potential to deliver novel analogs inaccessible by semisynthesis (or other means) but are confronted with the intrinsic complexity of natural products. In this lecture, I will describe the chemistry effort ongoing in our laboratory that attempts to respond to these challenges and explore the newly created opportunities.

Abstrakt: Many living organisms emit light, a phenomenon known as bioluminescence. The energy required for light production is generated by the oxidation of a small organic molecule, luciferin, catalyzed by a specific enzyme, luciferase. Luminous taxa have currently been reported from about 800 genera. The chemical nature and mechanisms of action of the few known types of bioluminescence substrates (luciferins) are as diverse as their phylogenetic distribution. Despite being widely used in reporter technologies, bioluminescent systems are largely understudied. Of at least forty different bioluminescent systems thought to exist in nature, molecular components of only ten light-emitting reactions are known, and the full biochemical pathway leading to light emission is only understood for two of them. In this talk, the current status and perspectives, in the context of postgenomic era, of novel bioluminescence systems including fungi, earthworms and marine polychaetes will be reviewed.

Literatura:
[1] Z. M. Kaskova, F. A. Dörr, V. N. Petushkov, K. V. Purtov, A. S. Tsarkova, N. S. Rodionova, K. S. Mineev, E. B. Guglya, A. Kotlobay, N. S. Baleeva, M. S. Baranov, A. S. Arseniev, J. I. Gitelson, S. Lukyanov, Y. Suzuki, S. Kanie, E. Pinto, P. Di Mascio, H. E. Waldenmaier, T. A. Pereira, R. P. Carvalho, A. G. Oliveira, Y. Oba, E. L. Bastos, C. V. Stevani, I. V. Yampolsky. Sci. Adv. 3, e1602847 (2017)
[2] A. S. Tsarkova, Z. M. Kaskova, I. V. Yampolsky. Acc. Chem. Res. 2016, 49 (11), 2372.
[3] Z. M. Kaskova, A. S. Tsarkova, I. V. Yampolsky. Chem. Soc. Rev., 2016, 45, 6048.
[4] Purtov KV, Petushkov VN, Baranov MS, Mineev KS, Rodionova NS, Kaskova ZM, Tsarkova AS, Petunin AI, Bondar VS, Rodicheva EK, Medvedeva SE, Oba Yuichi, Oba Yomiko, Arseniev AS, Lukyanov S, Gitelson JI, Yampolsky IV. Angewandte Chemie International Edition. 2015, 54, 8124.
[5] MA Dubinnyi, ZM Kaskova, NS Rodionova, MS Baranov, AY Gorokhovatsky, A Kotlobay, KM Solntsev, AS Tsarkova, VN Petushkov, IV Yampolsky, Angew. Chem. Int. Ed. 2015, 54, 7065.
[6] A.A. Kotlobay, K.S. Sarkisyan, Y.A. Mokrushina, M. Marcet-Houben, E.O. Serebrovskaya, N.M. Markina, L.G. Somermeyer, A.Y. Gorokhovatsky, A. Vvedensky, K.V. Purtov, V.N. Petushkov, N.S. Rodionova, T.V. Chepurnyh, L.I. Fakhranurova, E.B. Guglya, R. Ziganshin, A.S. Tsarkova, Z.M. Kaskova, V. Shender, M. Abakumov, T.O. Abakumova, I.S. Povolotskaya, F.M. Eroshkin, A.G. Zaraisky, A.S. Mishin, S. V. Dolgov, T.Y. Mitiouchkina, E.P. Kopantzev, H.E. Waldenmaier, A.G. Oliveira, Y. Oba, E. Barsova, E.A. Bogdanova, T. Gabaldón, C.V. Stevani, S. Lukyanov, I.V. Smirnov, J.I. Gitelson, F.A. Kondrashov, I.V. Yampolsky. PNAS 2018, 115, 12728

Non-canonical Wnt/planar cell polarity (PCP) signaling is a universal molecular machinery that controls cell polarization. We have shown that PCP signaling controls migration and drives pathogenesis of chronic lymphocytic leukemia (CLL). In my seminar I will discuss how PCP can be therapeutically targeted and show evidence that it is a relevant therapeutic target. I will focus on several specific questions:

• What is the potential of the inhibition of casein kinase 1 (CK1), a key component of noncanonical Wnt signaling pathways, in the treatment of CLL?
• How can we identify novel druggable targets in PCP pathway/cell migration using proteomics?
• Development of novel CK1 inhibitors (in collaboration with K. Paruch, Dept. Chemistry, Fac. Sci. MUNI) and their validation in the preclinical models.
• What other pathological conditions can benefit from PCP/CK1 inhibition?

Literatura:
[1] M. Kaucká, K. Plevová, Š. Pavlová, J. Verner, J. Procházková, P. Janovská, P. Krejčí, J. Kotašková, P. Ovesná, B. Tichý, Y. Brychtová, M. Doubek, A. Kozubík, J. Mayer, Š. Pospíšilováand V. Bryja: The planar cell polarity pathway drives pathogenesis of chronic lymphocytic leukemia by the regulation of B-lymphocyte migration, Cancer Research 73(5):1491-1501, 2013.
[2] Janovska P, Poppova L, Plevova K, Plesingerova H, Behal M, Kaucka M, Ovesna P, Hlozkova M, Borsky M, Stehlikova O, Brychtova Y, Doubek M, Machalova M, Baskar S, Kozubik A, Pospisilova S, Pavlova S, Bryja V.: Autocrine signaling by Wnt-5a deregulates chemotaxis of leukemic cells and predicts clinical outcome in chronic lymphocytic leukemia, Clinical Cancer Research 22(2):459-69, 2016.
[3] Janovska P, Verner J, Kohoutek J, Bryjova L, Gregorova M, Dzimkova M, Skabrahova H, Radaszkiewicz T, Ovesna P, Vondalova Blanarova O, Nemcova T, Hoferova Z, Vasickova K, Smyckova L, Egle A, Pavlova S, Poppova L, Plevova K, Pospisilova S, Bryja V.: Casein kinase 1 is a therapeutic target in chronic lymphocytic leukemia, Blood 131(11):1206-1218, 2018.
[4] Harnoš J, Cañizal MCA, Holler C, Jurásek M, Dublad J, Gömöryová K, Hanáková K, Bernatík O, Trantírek L, Gybeľ T, Fiedler M, Ryneš J, Dave Z, Fernandez-Llamazares AI, Zdráhal Z, Tripsianes K, Vácha R, Schambony A, Hoffmann C, Bryja V.: Dishevelled-3 protein conformation dynamics analyzed by FRET-based biosensors: a key role of casein kinase 1, Nature Communications 10(1):1804, 2019.