1. Synthesis of p38α MAP
kinase inhibitors
By: Vita Koren (100481835)

2. Introduction – The MAP kinase Pathway
 Enzymes that catalyze the
transfer of a phosphate
from ATP to the needed
molecule
 Involved in growth,
proliferation,
differentiation and
apoptosis of cells
 Cancer invasion = loss of
control of the above
functions
2
Dhillon, A., Hgan, S., Rath, O. and Kolch, W. (2007). MAP kinase signalling pathways in cancer. Oncogene. 26: 3279-3290

3. The p38α Component of MAP kinase
p38α------------------
3Roux, P and Blenis, J. (2004). ERK and p38 MAPK-Activated Protein Kinases: a Family of Protein Kinases with Diverse Biological Functions. Microbiol
Mol Biol Rev. 68(2): 320-344
 Activated during the secondary phosphorylation
 Important role in regulation of cytokine production in
response to stress
TNF-α
IL-1β
 Promotes diseases
Rheumatoid Arthritis
Type 1 Diabetes
Cancer

4. Previously Discovered Inhibitors
 Several inhibitors have been
found
 p38α is sensitive to these
inhibitors at submicromolar
IC50 values
4Alessi, D., Cuenda, A., Cohen, P., Dudley, D. and Saltiel, A. (1995). PD 098059 Is a Specific Inhibitor of the Activation of Mitogen-Activated Protein Kinase
Kinase in Vitro and in Vivo. Biol Chem, 270: 27488-27494

5. Potency of Experimental Molecule
 Goal: Develop and optimize stable methodology for the preparation
of an initial scaffold which can be applied towards drug development
of modified new p38α MAP kinase inhibitor
5Baur, B., Storch, K., Martz, K., Goettert, M., Richters, A., Rauh, D. and Laufer, S. (2013). Metabolically Stable Dibenzo[b,e]oxepin-11(6H)-ones as
Highly Selective p38 MAP Kinase Inhibitors: Optimizing Anti-Cytokine Activity in Human Whole Blood. MedChem. 8561-8578
vs.

6. Proposed Synthesis
6

7. Protection of Alcohol
Reaction TBDMSCl (equiv.) Et3N (equiv.) Yield (%)
1 (air) 1.0 4.0 43
2 (argon) 1.0 4.0 0
3 (air) 0.9 4.5 55
7
Green, T. and Wuts, P. (1999). Protective Groups in Organic Synthesis. Wiley-Interscience, New York, 127-141, 708-711
Reaction TBDMSCl (equiv.) Et3N (equiv.) Yield (%)
1 (air) 1.0 4.0 43
2 (argon) 1.0 4.0 0
3 (air) 0.9 4.5 55

8. Procedure
8

9. 1H NMR Spectra
9

10. Oxidation of the Alcohol
10
1. Corey, E. and Suggs, J. (1975). Pyridinium chlorochromate is a readily available, stable reagent, that oxidizes a wide variety of alcohols to carbonyl
compounds with high efficiency. Tetrahedron Lett. 16: 2647-2650
2. Rowlands, G. (2002). Oxidation and Reduction. Sussex. Retrieved from: http://www.massey.ac.nz/~gjrowlan/oxid/alco.pdf
3. Bolm, C., Magnus, A. and Hildebrand, J. (2000). Catalytic Synthesis of Aldehydes and Ketones under Mild Conditions Using TEMPO/Oxone. Organic
Lett. 2(8): 1173-1175
Reaction Reagents
(equiv.)
Solvent Temperature Time Yield (%)
1 Ca(ClO)2 (0.67) MeCN
Acetic acid
H2O
0ºC 1 hr 20
2 MnO2 (1.1) Hexane -10 ºC 3 hrs 0
3 PCC (1.5) DCM r.t 2 hrs 60

11. 1H NMR Spectra
11

12. Introduction of Phenylacetylene
Reaction Reagents (equiv.) Solvent Temperature Time Yield (%)
1 Phenylacetylene (5.0)
n-butyllithium (5.0)
THF -78ºCrt 2 hrs 0
2 Phenylacetylene (1.3)
Zinc iodide (2.5)
Triethylamine (2.5)
Toluene 80ºC 30 mins 44
12
1.Taylor, C and Bolshan, Y. (2014). Metal- free synthesis of ynones from acyl chlorides and potassium alkynyltrifluoroborate salts. OrgLett. 16(2): 488-491
2.Yuan, J., Wang, J., Zhang, G., Liu, C., Qi, X., Lan, Y., Miller, J., Kropf, A., Bunel, E. and Lei, A. (2015). Bimetallic zinc complex – active species in
coupling of terminal alkynes with aldehydes via nucleophilic addition/ Oppenauer oxidation. Chem Commun. 51: 576-579

13. 1H NMR Spectra
13

14. Proposed Mechanism
14

15. More Oxidations
Reaction Reagents
(equiv.)
Solvent Temperature Time Yield (%)
1 PCC (1.5) DCM r.t 2 hrs 65
15Corey, E. and Suggs, J. (1975). Pyridinium chlorochromate is a readily available, stable reagent, that oxidizes a wide variety of alcohols to carbonyl
compounds with high efficiency. Tetrahedron Lett. 16: 2647-2650

16. 13C NMR Spectra
16

17. Removal of the Protecting Group
17
Fuestro, S., Sancho, A., Acena, J. and Sanz-Cervera, J. (2009). Flurous TBAF: A convenient and selective reagent for fluoride-mediate deprotections. J. Org Chem. 74: 6398-6401
Reaction Reagents (equiv.) Solvent Temperature Time Yield (%)
1 Cs2CO3 (1.0) DMF/H2O 100ºC 1 hr 0
2 TBAF (1.5) DMF r.t 1 hr 0
3 TBAF (2.5) DMF r.t 3 hrs 0
4 HF (1.9) DMF r.t 1 hr 0
5 TBAF (1.1) DMF -10ºC 1 hr 0
6 HF-pyridine DMF r.t 40 mins 0

18. Conclusion
 Significant progress for the synthesis of initial scaffold for
an inhibitor of p38α MAP kinase has been made
 Protection, oxidation and propargylic alcohol addition was
accomplished
 The compound has never been synthesized and needs to be
optimized
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19. Future Direction
19
2 Steps 4 Steps

20. Acknowledgements
 A huge thank you to my supportive and
insightful supervisor Dr. Bolshan for all his help
inside and outside the laboratory
 Thank you to Kayla for always answering my
questions and providing great advice
 Pleasure working alongside all of my lab
companions: Ifedi, Stefan, Dylan and William
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