Research in the Kornienko Group
The unifying theme of Kornienko’s research projects is the discovery of novel synthetic organic chemistry and its utilization for anticancer drug discovery. For example, in one of the ongoing projects we discovered a new multicomponent reaction allowing for the construction of a pyrrole ring and applied it to the first general total synthesis of marine alkaloid rigidins (A below). The synthesis facilitated further synthetic and biological studies, which led to the discovery of a new anticancer scaffold based on the hypoxanthine core structure (B). These new agents are active at nanomolar concentrations against melanoma and glioblastoma, cancers with dismal clinical prognoses, and can now be made through a 4-component reaction in one step from commercially available reagents (B).
Our cancer drug discovery work emphasizes the development of innovative methods to combat apoptosis-resistant cancers, such as melanoma, glioblastoma, lung cancer, among others. Thus, much effort is applied toward the identification and investigation of natural products that exhibit antimetastatic properties at non-toxic concentrations or induce non-apoptotic cancer cell death, such as programmed necrosis, autophagy or paraptosis. We collaborate with a large group of cancer biologists and clinicians in the US and Europe. Examples of natural products, which are currently studied in Dr. Kornienko’s lab, are shown below.
Exploring Natural Product Chemistry and Biology with Multicomponent Reactions. 5. Discovery of a Novel Tubulin-Targeting Scaffold Derived from the Rigidin Family of Marine Alkaloids. Frolova, L. V.; Magedov, I. V.; Romero, A. E.; Karki, M.; Otero, I.; Hayden, K.; Evdokimov, N. M.;Banuls L. M. Y.; Rastogi, S. K.; Smith, W. R.; Lu, S. L.; Kiss, R.; Shuster, C. B.; Hamel, E.; Betancourt, T.; Rogelj, S.; Kornienko, A. J. Med. Chem. 2013, in press.
Metal-FreeTransannulation Reaction of Indoles with Nitrostyrenes: A Simple Practical Synthesis of 3-Substituted 2-Quinolones. Aksenov, A. V.; Smirnov, A. N.; Aksenov, N. A.; Aksenova, I. V.; Frolova, L. V.; Kornienko, A.; Magedov, I. V.; Rubin, M. Chem. Commun. 2013, in press.
Fischerindoline, a Pyrroloindole Terpenoid Isolated from Neosartorya pseudofischeri, with In Vitro Growth Inhibitory Activity in Human Cancer Cell Lines. Masi, M.; Andolfi, A.; Mathieu, V.; Boari, A.;Cimmino, A.;Banuls, L. M. Y.;Vurro, M.;Kornienko, A.; Kiss, R.;Evidente, A. Tetrahedron 2013, 69, 7466.
Perspective: Therapeutic Agents Triggering Non-Apoptotic Cancer Cell Death. Kornienko, A.; Mathieu, V.; Rastogi, S.; Lefranc, F.; Kiss, R. J. Med. Chem. 2013, 56, 4823.
Antiproliferative Activity of 2,3-Disubstituted Indoles Toward Apoptosis-Resistant Cancers Cells. Magedov, I. V.; Lefranc, F.;Frolova, L. V.;Banuls, L. M. Y.;Peretti, A. S.;Rogelj, S.;Mathieu, V. ;Kiss, R.;Kornienko, A. Bioorg. Med. Chem. Lett. 2013, 23, 3277.
Ophiobolin A induces paraptosis-like cell death in human glioblastoma cells by decreasing BKCa channel activity. Bury, M.;Girault, A.; Mégalizzi, V.;Spiegl-Kreinecker, S.;Mathieu, V.;Berger, W.;Evidente, A.: Kornienko, A.;Gailly, P.;Vandier, C.;Kiss, R. Cell Death Dis. 2013, 4, e569.
Narciclasine as well as other Amaryllidaceae Isocarbostyrils are Promising GTPase-Targeting Agents against Brain Cancers. Van Goietsenoven, G. ; Mathieu, V. ; Lefranc, F. ; Kornienko, A.; Evidente, A. ; Kiss, R.Med. Res. Rev. 2013, 33, 439.