Please use this identifier to cite or link to this item: http://scholarbank.nus.edu.sg/handle/10635/16882
Title: Design and synthesis of cysmethynil and analogues as inhibitors of isoprenylcysteine carboxyl methyltransferase (ICMT)
Authors: LEOW JO LENE
Keywords: Isoprenylcysteine carboxyl methyltransferase, Icmt, cysmethynil, indole analogues, anticancer, prenylation
Issue Date: 31-Jul-2009
Source: LEOW JO LENE (2009-07-31). Design and synthesis of cysmethynil and analogues as inhibitors of isoprenylcysteine carboxyl methyltransferase (ICMT). ScholarBank@NUS Repository.
Abstract: The objective of this thesis was to investigate the chemotherapeutic potential of a group of compounds with an indole core structure as isoprenylcysteine carboxyl methyltransferase (Icmt) inhibitors. Ras proteins contain a C-terminal CaaX motif which direct the proteins through a three-step post-translational process termed prenylation, in which Icmt catalyzes the last step methylation of the C-terminal prenylcysteine. Inhibition of Icmt has multiple impacts on cellular signaling processes<br>which ultimately leads to cell death. <br>The lead Icmt inhibitor, cysmethynil, was identified from a screen of a diverse chemical library of 10,000 compounds. An SAR study was first carried out on the indole core compounds discovered from the library, using different methods, namely the (i) PCA and PLS, (ii) multiple linear regression and (iii) CoMFA. All three approaches complement each other, and identified the steric factor to be important for activity. Improved activity was predicted by incorporation of a bulky side chain at position 1 of the indole ring while a smaller substituent at the position 5 phenyl ring was preferred for Icmt inhibition activity.<br>Lead optimization efforts guided by the SAR results were performed together with conventional analogue design approach. The compounds synthesized were classified according to (i) substitution on position 1 (Series 1), (ii) alteration at position 5 (Series 2), and (iii) modification of the acetamide side chain at position 3 (Series 3: tertiary amides, Series 4: amines and Series 5: homologues and<br>bioisosteres). A 6th series consisted of compounds with modification made at more than one position (1, 3 and/or 5). <br>The synthesized compounds were evaluated for Icmt inhibition activity and effects on the viability of human breast cancer cells. Good correlation was observed between the two activities, with the exception that the amine analogues (Series 4) were significantly more potent than the other series.<br>Computational methods were employed to analyze the results from the Icmt inhibitory activity, on the 47 compounds synthesized. A pharmacophore model was first developed identifying aromatic and hydrophobic groups as the main features of the indole based Icmt inhibitors, and a H bond acceptor group as the only polar feature in the model. QSAR analysis was also carried out on the same set of biological data using multiple linear regression, MOEb's AutoQsar and Sybylb's CoMFA/CoMSIA. The models complement each other and also agreed with the pharmacophore model, where size and hydrophobicity was determined to be the main contributor to activity. Visualization of the steric field from CoMFA identified that substituent at position 1 and 5 provides the bulk important for activity. <br>To better understand the consequences of Icmt inhibition, the amino analogues identified as the most potent inhibitors thus far, were selected for further detailed biological evaluation. Prior studies have demonstrated that inhibition of Icmt by cysmethynil has resulted in various downstream effects such as cell cycle arrest and induction of autophagy, resulting in cell death. Investigation of these biological consequences were conducted on the selected amine analogues and they were found to be able to demonstrate the same effects at much lower doses.<br>In conclusion, the indole analogues are effective as Icmt inhibitors and are potentially useful as chemotherapeutic agents. The lead optimization effort has elucidated the amine analogues as Icmt inhibitors with significantly improved activity in cell-based studies, which may be used for further investigation of the outcome of Icmt inhibition and pre-clinical studies. The pharmacophore model generated using the synthesized library of compounds may be useful to screen against database of compounds that can be readily obtained for biological evaluation and further understand the consequences of Icmt inhibition
URI: http://scholarbank.nus.edu.sg/handle/10635/16882
Appears in Collections:Ph.D Theses (Open)

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