Design And Synthesis Of Piperidine Amines As L3MBTL1Antagonists

Epigenetics refers to heritable changes in gene functions that involves in chromatinand that do not entail a change in DNA sequence. Although all cells in an organisminherit the same genetic material, heritable differences in the packaging of DNA andchromatin enable cells to maintain distinguishing physical characteristics and biologicalfunctions. The research of epigenetics is of great significance in curing various diseasesthat have obsessed human beings for years, such as cancer, inflammation, and metabolicdisease.Covalent modification of histones and methylation of DNA play a vital role inchromatin dynamics and gene expression regulation. As a member of histonemodifications, lysine methylation in histone contributes to protein interactions as wellas gene expression regulation. As a result, crucial to chromatin regulation is therecognition of lysine methylation.MBT (The malignant brain tumor) domain seems to be unique in their selectivityfor lysine methylation. It is possible to design and synthesize several ligands for MBTdue to its specific binding to lysine-KMe (cavity insertion mode). Subsequently, wechoose MBT domain for our initial study on lysine methylation antagonists. L3MBTL1containing proteins are important to gene stability. It can inhibit tumor induced by bonemarrow dysfunction. Its consumption can promote human hematopoietic cells redsubdivision. However, the activity of L3MBTL1antagonists is unsatisfied so thatfurther studies are extremely necessary.Based on compound UNC669and the known structure of L3MBTL1pocket, wedesigned three series of compounds: pipecolinate ketone compounds,pyrrolo[2,3-d]pyrimidine compounds and hexahydropyrimido[4,5-d]pyrrolo[1,2-a]pyrimdine compounds, hoping to find potent antagonists. Six piperidine ketonecompounds were synthetized through four routes. Eleven pyrrolo[2,3-d]pyrimidinecompounds were synthetized through one route. Eight hexahydropyrimido[4,5-d]pyrrolo[1,2-a] pyrimdine were synthetized through tworoutes. We finally synthesized25compounds via7different routes.With the help of Prof. Frye (UNC), these compounds were tested byAlphaScreen/ITC and some of them showed moderate activity for L3MBTL1. Amongall the tested compounds, compound2-29c was found to be the most active to inhibitL3MBTL1with the IC50values of2.6±0.79μM which is slightly better than UNC926(IC50=3.9±1.1μM). For hexahydropyrimido[4,5-d]pyrrolo[1,2-a]pyrimdine compounds,only compound2-38a showed the low activity (IC50=38±3.2μM). However, on thebasis of the result we can make some further design, expecting to get better L3MBTL1antagonists.We further understand the pocket of L3MBTL1and design of L3MBTL1antagonists via studying L3MBTL1antagonists, providing the basis for finding betterL3MBTL1antagonists in following work.