Development of mitotic kinesin inhibitors composed of photochromic compounds as anti-cancer drug Abstract


Development of mitotic kinesin inhibitors composed of photochromic compounds as anti-cancer drug

Abstract:

Kinsen is a molecular motor protein that moves carrying organelles directly along microtubules uses ATP hydrolysis. Recently in Bio nanotechnology, based on kinesin and microtubules, attention is being focused on the application of molecular shuttles to drug delivery system. The kinesin Eg5, is a one of the kinesin-5 family, in recent years, mitotic kinesins Eg-5 brings attention as new targets for cancer therapy due to its function during the eukaryotic cell division, studies show that kinesin Eg5 mitotic motor function is required for the assembly of bipolar spindles and the efficient separation of centrosomes in HeLa cells. A large number of Eg-5 inhibitors have been reported in the scientific and patent literature. Many inhibitors of Eg5 have been developed and designed in soka university and prepare highly efficient of photo switch with the kinesin within the drug. The drug will contain Photochromic compounds that mimic Eg5-specific inhibitors and photocontrol Eg-5.

Introduction:
Mitosis is a fundamental process during cell division, the mitotic spindle is center to this process. Chromosome segregation occurs on a bipolar spindle structure that is built from microtubules. Medication inhibitor that target mitotic-spindle and microtubules are among the most effective cancer therapeutics. Kinesins are a family of molecular motors, currently being as drug targets, due to their many roles in intracellular transport of cell division. Eg5 (also known as kinesin-5 or kinesin spindle protein) has a role to formation and maintenance of the bipolar mitotic spindle. This motor protein has important functions during mitosis, such as chromosome segregation and cytokinesis (see fig.1).

The results of studies show that Eg5 inhibitor arrest cell cycle and leading to cancer cell death by apoptosis. previously shown that Eg5 inhibitors bind to the L5/?2/?3 pocket like STLC bind to allosteric pocket of the Eg5 motor which induces the deformation of the ATP binding pocket and this would provide useful information can contribute in anticancer drugs. 1
Figure.1: Eg5 structure and function. 2
Methodology:

Eg5 to drive centrosome separation and bipolar spindle assembly during cell division, making Eg5 an attractive target for anti-cancer therapies. S-Trityl-L-cysteine (STLC) is well known as an inhibitor of Eg5. STLC and monastrol bind on the Eg5 motor well known site.
Azobenzene is a photochromic molecule that change rapidly undergo the reversible of isomerization between the cis and trans forms in response to light ultraviolet (UV) and visible (VIS) irradiation. 4
Figure.2: Structural formula of the azobenzene derivative BPSBA 5.

(ACTAB) consists of many components a trityl group, N-acetyl-L-cysteine and azobenzene which slow down the activity of ATPase and motor activities. in my opinion we can use liposomes as a drug carrier for improving delivery of cancer therapy, its suitable for delivery of hydrophilic and hydrophobic. In vivo using liposome, the cell membrane permeability of the drug vehicles is examined by monitoring the inhibition of mitosis of Hela cell. 1

Figure.3: A simplified diagram illustrating drug–receptor binding. 6

The aim of this research:
1- Design and develop a drug delivery system for the cancer therapy.
2- Photo Control the cell divisions through the photochromic kinesin Eg5 until reach to cancer cell death.
3- Design a delivery vehicle containing the inhibitor of kinesin.

RESEARCH PLAN
1. Development of novel inhibitors of mitotic kinesin Eg5 as an anti-cancer drug which have photo-switching mechanism.
(1-1) Design and synthesis of novel inhibitors of mitotic kinesin Eg5 composed of photochromic compounds.
(1-2) Analysis of inhibitory effect of the photochromic inhibitor on the ATPase activity of Eg5.
(1-3) In vitro motility assay to show the inhibitory effect of the photochromic inhibitor on the motor activity of Eg5.
(1-4) Kinetic study on the Eg5 ATPase cycle by studying the effect of the photochromic inhibitor.

Conclusion:

Biotechnology advances are leading to improved medications that can target diseases more effectively, Drug delivery is an effective way that can solve the problem of cancer patient, and this technology is rare in Arab world. so, if the research will be done that will bring a great evaluation in cancer therapy without side effect instead of chemotherapy which could reduce a lot of pain on the cancer patient not just in Syria but in all over the world. By arrest cancer cell cycle using inhibitor of Eg-5 during cell division. Mr. Maruta in soka university previously showed that the it is possible to control the function of kinesin using a photochromic azobenzene derivative. He had demonstrated that the ATPase activity of the motor protein of kinesin Eg5 is photo regulated using incorporation method of photochromic molecules.