Professor Mary Jane Meegan

Summary

This research project will examine the molecular design, chemistry and biochemical activity of some heterocyclic derivatives of 3,4,5-trimethoxystyrene as microtubule binding agents, with potential therapeutic use as anticancer agents in breast cancer. Advances in breast cancer research have established the existence of clinical disease sub-types, each with distint pathologies, course of disease progression and response to therapeutic intervention. Survival outcomes have increased dramatically in recent years for estrogen receptor(ER) positive disease largely due to the routine use of the antiestrogen tamoxifen or aromatase inhibitors such as anastrazole. However, significant disease subtypes such as "triple negative " breast tcancer (lacking expression of ER, progesterone or HER-2 receptor; approx 15% of cases) present a difficult challemge with standard chemotherapy having little impact on overall survival. Treatment of HER-2 positive breast cancer, a sub-type characterised by frequent metastatic progression is also clinically challenging although agents such as the moniclonal antibody trastuzumab have proved very useful. There is an ongoing clinical requirement for the identification of more targeted and selective agents as potential breast cancer drugs for the various breast cancer groups. Microtubule binding agents (MBAs) are an important category of anticancer drugs aiming to inhibit the assembly of tubulin to microtubules or the disassembly of microtubules to tubulin, thus blocking the cell division. Among all the natural products that possess such mechanism of action, colchicine and combretastatin A-4 have driven the interest of many research groups, due to their structural simplicity and antiproliferative activities. This project will focus on the design of heterocyclic amide derivatives of combretastatin A-4. The compounds identified for synthesis in this research group are a new series of heterocyclic derivatives of the 3,4,5-trimethoxystyrene scaffold having increased water solubility, and therefore are very suitable chemical scaffolds for development as potential biologically active compounds.

Project Type

Interdisciplinary Research

Person Months

48

Summary

Cancers of the lymphatic cells (lymphomas) account for approximately 12% of malignant diseases worldwide and 80% of these cases are subdivided into non-Hodgkin's lymphomas (NHL). As part of an ongoing research project we have sought to identify possible alternatives to the current clinical drugs used in the treatments for chronic lymphocytic leukaemia(CLL). We have recently discovered structural derivatives of the anti-depressant drug maprotiline which are effective against Burkitt's lymphoma and related lymphomas and are potential new targets for the design of compounds with activity against chronic lymphocytic leukaemia(CLL). We have previously demonstrated that a series of these maprotiline related 9,10-ethanoanthracenes express significant antiproliferative effects in vitro in two BL cell lines: EBV- MUTU-I and the chemoresistant EBV+ DG75 lymphoma cell lines. The objective of this project is the design and evaluation of novel small molecules which target chronic lymphocytic leukaemia(CLL). Based on our previous studies, a small focussed library of structurally related anthracene and related compounds will be designed and chemically characterised. Many of these compounds contained a classic nitrostyrene or unsaturated ketone core which have also been previously shown to possess activity in the Burkitt lymphoma cell lines. In this project the structures proposed for investigation are based on the anthracene and related ethano-anthracene scaffolds. These compounds will be synthesised via a number of established routes and each compound will be subsequently characterised by spectroscopic methods (1H and 13C NMR, IR and HRMS). The antiproliferative activities of the compounds will be evaluated using two EBV-transformed CLL cell lines PGA and HG3. A possible mechanism of action for the compounds will be investigated. The structure activity relationships for the series of products will also be examined.

Project Type

Interdisciplinary Research

Person Months

48

Summary

This project will examine the chemistry and biochemical activity of novel fluorinated -lactam molecules and will assess their potential anticancer activity. Naturally occurring and synthetic β-lactams (azetidin-2-ones) are best known for their potent antibacterial activities. Molecules containing the azetidinone (β-lactam) heterocycles have also been demonstrated to have additional alternative potent and interesting activities, and occupy a central place among medicinally important compounds. Examples of the azetidin-2-one scaffold have recently been investigated as cytotoxic agents and as inhibitors of proteases such as leukocyte elastase, gelatinases and tryptases. Many nitrogen containing heterocyclic compounds e.g thiazoles, pyrroles, indoles etc. have been designed as tubulin targetting agents which bind to tubulin and disrupt mitosis in cancer cells. We have previously demonstrated that the azetidin-2-one(β-lactam) ring structure can be modified to result in compounds with potent antitumour activity in a wide range of cancer cell lines, e.g. breast, lung, prostate and leukaemia cell lines. These compounds also result in cell cycle arrest at the G2/M phase. In this project, the use of the four-membered nitrogen heterocycle azetidin-2-one (β-lactam) ring as a scaffold for bioactive compounds is investigated in an effort to gain access to novel therapeutic agents that possess vascular targeting and potent anticancer effects in tumour cells. The specific effects on biological activity of the introduction of a fluorine substituent on the azetidinone scaffold will be investigated to optimise the potency of selected examples.

Project Type

Interdisciplinary Research

Person Months

24

Summary

Glucuronidation by uridine 5-diphosphoglucuronosyl transferase enzymes (UGTs) is a cause of intrinsic drug resistance in cancer cells. Glucuronidation of combretastatin A-4 (CA-4) was previously identified as a mechanism of resistance in hepatocellular cancer cells. In the project we propose chemical manipulation of b- lactam bridged analogues of Combretastatin A-4 as a novel means of overcoming drug resistance associated with glucuronidation due to the expression of UGTs in the CA-4 resistant human colon cancer HT-29 cells. The alkene bridge of CA-4 is replaced with a b-lactam ring to circumvent potential iso- merisation while the potential sites of glucuronate conjugation are deleted in the novel 3-substituted- 1,4-diaryl-2-azetidinone analogues of CA-4. We hypothesise that glucuronidation of CA-4 is the mech- anism of drug resistance in HT-29 cells. Ring B thioether containing 2-azetidinone analogues of CA-4 such as 4-(4-(methylthio)phenyl)-3-phenyl-1-(3,4,5-trimethoxyphenyl)azetidin-2-one (27) and 3- hydroxy-4-(4-(methylthio)phenyl)-1-(3,4,5-trimethoxyphenyl)azetidin-2-one (45) were identified as the most potent inhibitors of tumour cell growth, independent of UGT status, displaying antiproliferative activity in the low nanomolar range. These compounds also disrupted the microtubular structure in MCF- 7 and HT-29 cells, and caused G2/M arrest and apoptosis. Taken together, these findings highlight the potential of chemical manipulation as a means of overcoming glucuronidation attributed drug resistance in CA-4 resistant human colon cancer HT-29 cells, allowing the development of therapeutically superior analogues.

Funding Agency

King Abdul Aziz University - Jeddah, Saudi Arabia

Project Type

Interdisciplinary Research

Person Months

48