Design and synthesis of pictet–spengler condensation products that exhibit oncogenic-ras synthetic lethality and induce non-apoptotic cell death

Abstract

a b s t r a c t A series of Pictet-Spengler condensation derivatives (tetrahydro-b-carbolines) was designed, synthesized and evaluated for lethality against a panel of seven cancer cell lines. Seven compounds (2a, Pictet-Spengler condensation derivatives, known as tetrahydrob-carbolines, have been investigated as agents for treating human diseases, including cancer. The tricyclic tetrahydro-b-carboline ring structure is a motif in both natural and synthetic cytotoxic compounds that can act through multiple mechanisms. 1 Among the tetrahydro-b-carboline compounds that display potent cytotoxicity against numerous cancer cell lines are harman and norharman derivatives, During the last two decades, there has been a tremendous increase in interest in developing more effective treatment strategies for cancer, as traditional chemotherapeutic agents exhibit toxic side effects and induce drug resistance. 18 MEL24 is selectively lethal to immortalized cancer cells and induces cell death by stabilizing the tumor-suppressor p53. Considering that both MEL24 and RSL3 contain the privileged 1,2,3,4-tetrahydro-b-carboline moiety, but quite different substitution patterns, we wondered whether it would be possible to transform the MEL24 scaffold from an Mdm2-MdmX inhibitor to a oncogenic-RAS selective lethal compound, by altering the substitution around the tetrahydro-b-carboline moiety. Towards this end, we designed and synthesized novel tetrahydro-b-carboline derivatives including: (i) 5-(2,9-dihydro-1H-pyrido [3,4-b]indol-1-yl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (semi-oxidized) and 1, 3-dimethyl-5-(9H-pyrido[3,4-b]indol-1-yl) pyrimidine-0960-894X/$ -see front matter