1. Synthesis of Pyridyl
Biphenylmethylene analog by
Suzuki cross-coupling: A novel
CYP17A1 enzyme inhibitor
Name: L.D. Mthembu
Student no: 20800809
Supervisor: Mr N.J. Gumede
B-Tech Chemistry (IV) Project
Institution: Mangosuthu University of Technology

2. Contents
1) Introduction
2) Aims
3) Methodology
4) Results and Discussion
5) Conclusion
6) Future Task
7) Acknowledgements

3. Introduction
• Prostate cancer is a leading cause of cancer death
worldwide. Therefore, blockage of androgen production in
testes adrenals is a promising strategy for the treatment of
prostate cancer through CYP17 inhibition[1].
• Inhibition of this enzyme would enable the decrease in the
production of androgens from testicular and adrenal
androgens[2].
• The 4-[(3’, 4’-Dimethoxybiphenyl-4-yl)methyl]pyridine
(Target molecule) is a novel CYP 17 inhibitor. It was found
to be selective, highly potent CYP17 inhibitor compared to
abiraterone acetate in terms of activity and selectivity[3] .
• The target molecule belongs to a class of nonsteroidal
inhibitors.
[1] Heinlein, C. A.; Chang, C. Endocr. Rev. 2004, 25, 276−308.
[2] S. Nakajin, J.E. Shively, P.M. Yuan, P.F. Hall, Biochemistry, 20 (1981) 4037–4042.
[3]Hu Q.; Jagusch C.; Hille U.E.; Haupenthal J.; and Hartmann R.W. Journal of Medicinal Chemistry article, 2010, 53, 5749.

4. Fig. 1 Structure of 4-[(3’, 4’-Dimethoxybiphenyl-4-yl)methyl]pyridine

5. Overall Reaction

6. Step 1: Oxidative addition
Reaction Mechanism

7. Step 2: Transmetalation

8. Step 3:Reductive elimination

9. Aims
• To synthesize 4-[(3’, 4’-Dimethoxybiphenyl-4-
yl)methyl]pyridine by Suzuki cross-coupling.
• Purification of the product using Column Chromatography.
• Structure elucidation using Fourier Transform Infra Red
Spectroscopy, Ultraviolet-visible spectroscopy and Nuclear
magnetic resonance spectroscopy.
• Quantum Mechanical calculations to illustrate the
electronic features that are important in the reactivity of
these molecules.

10. Binding mechanism of enzyme-ligand interaction.

11. Materials Mass(g) Volume
(ml)
4-(4-chlorobenzyl)pyridine 0.25 0.22
Toluene - 20
Sodium carbonate 21.198 12.8
65% Ethanol - 12.8
3,4-dimethoxyphenylboronic
acid
0.34 -
Tetrabutylammonium
bromide
0.34 0.33
Palladium acetate 0.05
Ethyl acetate - 20
Water - 10
Brine - 20
• Mixture was deoxygenated
under reduced pressure
and flushed with nitrogen
• Reflux for 4hrs, cooled
• Dried over with sodium
sulphate
• Filtered over a short plug
of celite
• Evaporated under reduced
pressure
Methodology

12. Purification procedure
• Column chromatography technique was used for the
purification of the product that was synthesized.
• Silica gel was used as the stationary phase and
water/ethanol (1:2) mixture was used as the solvent
(mobile phase).
• This technique was used to remove impurities in the
compound that was synthesized.

13. Percentage yield and efficiency of a reaction
• Percentage yield
= (actual yield/theoretical yield)
X 100
= (0.2991 g/0.4025 g) X 100
= 74.3%
• % Atom Economy
= (FW of atoms utilized/FW of all
reactants) X 100
= (305.37036/371.62246) X 100%
= 82.2%

14. Density Functional Theory (DFT) Calculations.
• The Quantum Mechanical/Molecular Mechanics
(QM/MM) calculations were performed by using Jaguar
(v7.9)[4].
• A DFT optimization procedure was used to calculate
electronic properties related to the reactivity of molecules
in the pharmacophore model developed. The B3LYP 6-
31G* was used as a basis set function in our DFT
calculation.
• The optimization was then followed by a single-point
energy calculation at the optimum geometries to obtain
aqueous solution phase energies using a continuum
treatment of solvation Poisson-Boltzmann (PBF) model.
[4]. Jaguar, version 7.9, Schrödinger, LLC, New York, NY, 2012

15. Results and Discussion
Figure 2: FTIR Spectrum for a synthesized impure compound under study.

16. Figure 3: FTIR Spectrum for a purified compound under study.

17. Table 1: Frequencies of the functional group present in
the spectrum for the pure compound in figure 2.
Functional group Frequency (cm-1)
N-H stretching 3355.2
Aromatic stretching 3017
C-H stretching 2961
C-H stretching 2833.8
C=C (aromatic) 1605.2
C=C (aromatic) 1414.5
C-O-C stretching 1256.8
C-O-C stretching 1071
C-H Bend 788.76
N-H bend 608.17

18. Protonated state Neutral state

19. Figure 4: UV-VISIBLE spectrum for the synthesized compound

20. Figure 5: H NMR scans for the synthesized and theoretical molecule

21. Figure 6. DFT results for the active molecule. Orbital diagrams of (a) HOMO and (b) LUMO,
mapped onto the structure. (c) 3D-contours of molecular electrostatic potential maps at -
30kcal/mol. Regions: high electronic density (negative potential) in red; low electronic density
(positive potential) in dark blue. (d) Interaction strength contours mapped onto the structure.
Groups that are susceptible to substitution (e.g. methoxy group ) are visible.
(a) HOMO (b) LUMO
(c) Molecular Electrostatic
potential
(d) Interaction strength

22. Conclusion
• The target molecule was successfully synthesized.
• This can be said based on the fact that a white solid was
obtained and qualitative analysis was conducted to prove
the identity of the product obtained.
• Quantum mechanical calculation shows that the target
molecule is highly reactive.

23. Future Task
• Study more about the enzyme
• Reaction between the enzyme inhibitor and enzyme

24. Acknowledgements
I would like to thank the following people who made my project
to be a success
• My God, alpha and omega
• My Family
• Mr N.J. Gumede(Supervisor)
• Mrs N. Msimango (M.U.T Chemistry Senior Industrial
Technician)
• Dr M.M. Shapi and Mr N.E. Damoyi
• Mr S.M. Nkosi
• And all M.U.T. Chemistry Laboratory staff who assisted me.

25. Any Questions?