Staurosporine

Discovery of a potential anti-cancer drug ?

Clive Walker

Clive's Homepage
Molecule of the Month Homepage


On this page:

Introduction Staurosporine structure 3D structure
Biological properties Compounds in development Chemistry

Introduction

Staurosporine is a natural product originally isolated in 1977 from the bacterium Streptomyces staurosporeus by Omura et al 1 . It was the first of over 50 alkaloids to be isolated with this type of chemical structure. The chemical structure of Staurosporine was elucidated by X-ray analysis of a single crystal 2 and the absolute stereochemical configuration by the same method in 1994 3 .

Staurosporine was discovered to have biological activities ranging from anti-fungal to anti-hypertensive 4 . The interest in these activities resulted in a large investigative effort in chemistry and biology and the discovery of the potential for anti-cancer treatment. This led to the chemical synthesis of Staurosporine itself 5,6 followed by the synthesis of compounds 7,8 that had increasingly diverse chemical structure and their biological assessment.

Structure of Staurosporine top
The chemical structure of Staurosporine can be divided into two units: a sugar molecule which has a unique stereochemical arrangement of atoms and a heterocyclic group which is planar.

The sugar part of Staurosporine is in blue. The rest of the structure is an indole carbazole sub-unit.

structure
3D Structure top

To view this interactive structure you need the Chime Plug-in which is available free. With this software you will be able to rotate and view the molecule in different ways with the mouse.

Right click : stop the structure rotating

Left click : you rotate the structure

Shift then left click and drag : zoom in or out

Once you have downloaded the Plug-in you can view the 3D version of this page.

Chime plug-in

Alternatively download the 3D structure pdb file and view with your modelling software, for example RASMol. See the Molecule of the Month Homepage for instructions.

Biological properties top

One biological activity of Staurosporine is the inhibition of kinase proteins. A kinase is an enzyme that is critically involved in cell signalling, the process which determines how a biological cell reacts to it's environment within the body. Cancer is typified by unregulated cell signalling leading to explosive cell growth. Inhibition of these cell processes could have anti-cancer effects.

Staurosporine exerts it's biological effect by interacting, or binding, with a biological target such as a kinase. The elucidation of the structure of Staurosporine bound to a protein kinase is shown below 9 . This image was obtained by crystallisation of the kinase with Staurosporine followed by x-ray diffraction .

Staurosporine binding Staurosporine is shown as green, blue and red circles and the protein kinase is shown in yellow and purple.

This image is from the Brookhaven database [1stc.pdb]

Thanks to my colleague Xiao-Ling Cockcroft for this picture.

Normally the kinase has another molecule called adenosine triphosphate, or ATP, bound to it. Staurosporine prevents ATP binding because it has a stronger 'affinity' for the kinase. Staurosporine has a broad spectrum of activity against a selection of kinases and this means that it is unlikely to be useful as an anti-cancer drug itself because it would interfere with other 'normal' cell processes.

Researchers set out to try and mimic the actions of Staurosporine and to produce compounds 7,8 that were more selective [ and had less side effects ]. These compounds, discovered after Staurosporine, have been developed as potential therapeutic agents.

Some compounds are now in clinical trials in Man as anti-cancer drugs and, if successful, these results will validate the biological rationale.

Compounds in development top
At first these new compounds were closely related to Staurosporine 10 but lately a number of new structural classes have been discovered.

Some of the newer compounds that have been developed are shown below:

compounds

They all originally derived from the Staurosporine structure or from investigation of kinase inhibition. It is a tribute to the ingenuity of the researchers that a wide range of structures have been found to be able to mimic the action of Staurosporine.

Chemistry top

Despite being isolated in 1977, with the structure determined in 1978, the first total chemical syntheses were achieved by the Danishefsky and Wood groups 5,6 in 1996 although fragments of the molecule were made before this. These syntheses chemically proved the absolute stereochemistry of Staurosporine.

There are a number of challenges in any synthesis of Staurosporine. Amongst these are joining the sugar and carbazole groups together, establishing the sugar stereochemistry and doing this in a way that is efficient and concise. Both syntheses use a wealth of chemical reagents and expertise to overcome the synthetic 'problems'.

Some of the key steps are shown below:

danishefsky chem

Another synthesis using a conceptually different approach was achieved by Wood and co-workers 6 , also in 1996. In this case a neat ring expansion reaction created the desired sugar group and gave Staurosporine in 19 steps.

wood chemistry
References top

1 S.Omura, Y.Iwai, A.Hirano, A.Nakagawa, J.Awaya, H.Tsuchiya, Y.Takahashi and R.Masuma, J.Antibiotics, 30, 275 [ 1977 ]

2 A.Furasaki, N.Hashiba, T.Matsumoto, A.Hirano, Y.Iwai, and S.Omura, J.Chem.Soc., Chem.Comm., 801 [ 1978 ]

3 N.Funato, H.Takayanagi, Y.Kouda, Y.Toda, H.Harigaya, Y.Iwai and S.Omura, Tetrahedron Letters, 35, 1251 [ 1994 ]

4 S.Omura, Y.Sasaki, Y.Iwai and H.Takeshimi, J.Antibiotics, 48, 535 [ 1995 ]

5 J.T.Link, S.Raghavan, M.Gallant, S.J Danishefsky, T.C.Chou and L.M.Ballas, J.Am.Chem.Soc., 118, 2825 [ 1996 ]

6 J.L.Wood, B.M.Stolz and S.N.Goodman, J.Am.Chem.Soc., 118, 10656 [ 1996 ]

7 P.M.Traxler, Exp.Opin.Ther.Patents, 7, 571 [ 1997 ]

8 L.M.Strawn and L.K.Shawver, Exp.Opin.Invest.Drugs, 7, 553 [ 1998 ]

9 L. Prade, R. A. Engh, A. Girod, V. Kinzel, R. Huber, D. Bossemeyer, Structure (London) 5, 1627 [ 1997 ]

10 A.Gescher, Gen. Phamac., 5, 721 [ 1998 ]
top

Updated December 2001