Design and synthesis of novel Eg5 inhibitors
Publication Type
Original research
  • Abualhasan, M.
  • Sutcliffe, O. B.
  • Kozielski, F.
  • Mackay, S. P.

The Currently present antimitotic drugs target directly microtubule building block, these drugs have neurotoxicity side effects and the Cells may develop resistance. New antimitotic drugs act indirectly on microtubules, these drugs have specific functions on phases of mitosis, and their inhibition may produce fewer side effects than tubulin drugs.
Eg5 motors are a member of the kinesin family which are required for spindle bipolarity maintenance. Inhibition of these motors induces mono-asters cells.
S-trityl-L-cysteine (STLC) is a specific and effective Eg5 inhibitor, the trityl group of the STLC binds to three hydrophobic sites inside the binding pocket[1].
Our aim is to design and synthesize high potency specific Eg5 inhibitors which have a higher inhibition activity than the STLC. Our suggested compounds have in general extended benzyl group, which is believed to be more flexible compared to the phenyl group of the STLC. It is also believed  the benzyl moiety will increase the hydrophobic binding to the Eg5 motors.
First of all benzyl analogues of STLC was docked into Eg5 using the GOLD algorithm, ten different poses were scored.
The syntheses of the different benzyl analogues consist mainly of two steps; first the synthesis the alcohol of the benzyl moiety using Grignard chemistry[2] the second is the coupling of alcohol to the cysteine conjugates.
The synthesized compounds were tested by ATPase and cell-based bioassays.
Molecular modelling shows that our suggested benzyl analogues bind to the same Eg5 binding site as STLC and the Gold scores showed good and promising results.
The ATPase and cell-based bioassays test results demonstrated high inhibition for most of the synthesised compounds some of them even have a higher inhibition activity compared to the STLC.
The synthesised benzyl derivatives has demonstrated a good inhibition activity by ATPase test in consensus with the modelling score results.
Future work is to synthesise more of benzyl analogues and also to determine the crystal structure of the most active compounds, this will give us a better understanding of the exact binding pattern of these compounds to the Eg5 motors.

Journal of Pharmacy and Pharmacology 2010, 62 (10), 1367
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