Synthesis

Results

Scheme 3. Proposed Synthetic Method for Formation of (11) 4

References

Table 1. Synthetic Yields

Acknowledgements

Experimental

Conclusions

Future Directions

Abstract

Figure 1. β-Aminopropionitrile (BAPN)

Objectives

• The solvent system is DCM, MeOH, or a combination ofboth and it is adjusted depending upon the solubility of thesubstrates.

• The synthesis of twelve different small-molecule LOXinhibitors was attempted.

Figure 2. Synthetic Targets

Solano Group Members: LOX Project Team

Raymond Martinez, Nkiruka Oragwam, Ana Sofía Potellá Pérez, Veronica Sanchez, John Spaeth, Worawith Techathaveewat

Funding

NSF under grant HRD-0331537 (CSU-LSAMP).

Ronald E. McNair Postbaccalaureate Achievement Program

Dr. Karlo Lopez’s Research Group

Lysyl oxidase (LOX) is a protein that is responsible for the proper

formation of collagen in a variety of animal species, including humans.

However, there is a correlation between the over-expression of the LOX

protein in hypoxic tumors and the metastasis of those tumors

throughout the body.1 β-Aminopropionitrile (β-APN) is a compound

capable of inhibiting the formation of LOX.2 Since LOX is required for

proper collagen formation, a method of delivery must be able to

selectively deliver β-APN to hypoxic tumors. Reductive amination is a

synthetic technique that can be used to make the outlined synthetic

targets.3

• Our optimized synthetic scheme works effectively with aldehydes and ketones.

• The molecules will be tested by collaborators in the LopezResearch Group to see if they decrease the activity of theLOX enzyme and this information will be used to increaseour understanding of how to design an effective drug.

• Current efforts are focused on establishing purity and yield for synthesized compounds.

• Explore oxygen-containing, and nitrogen-containing heterocyclic molecules for delivery of β-APN.

• Effectively synthesize reagents in-house, maximizing cost efficiency. (Addition of substituents to aromatic ring).

• Synthesis of prodrugs that selectively react in a hypoxicenvironment.

• Optimize synthesis of amines containing β-APN.

Scheme 1. Optimized Synthetic Method

Figure 4. Future β-APN Delivery Methods

1. Narayanan, A.; Siegel, R.; Martin, G. “On The Inhibition Of Lysyl Oxidase By β-Aminopropionitrile.” Biochem. Biophys. Res. Commun. 1972, 46, 745-751.

2. Granchi, C.; Funaioli, T.; Erler, J. T.; Giaccia, A. J.; Macchia, M.; Minutolo, F. “Bioreductively Activated Lysyl Oxidase Inhibitors against Hypoxic Tumours.” ChemMedChem. 2009, 4, 1590- 1594.

3. Chen, Y.; Hu, L. “Design of anticancer prodrugs for reductive activation.” Med. Res. Rev. 2009, 29, 29-64.

4. Bartoli, G.; Bosco, M.; Dalpozzo, R.; “Grignard Reagents Selective Attack to NitroarenicFunction in the Presence of Other Electrophilic Groups.” Tetrahedron Letters. 1985, 26, 115- 118.

Justin M. Thornton, Danielle M. SolanoDepartment of Chemistry, California State University Bakersfield, Bakersfield, CA

R1 R2 Product Yieldo-nitrobenzyl H (1) 7.6%

p-nitrobenzyl H (2) 44.96%

m-nitrobenzyl H (3) 13.57%

2-methoxy-4-nitrobenzyl

H (4) TBD

p-nitrobenzyl CH3 (5) TBD

m-nitrobenzyl CH3 (6) 2.58%

p-nitrobenzyl Ph (7) TBD

Methyl-4-formylbenzyl

H (8) 16.43%

4-bromobenzyl H (9) TBD

5-nitro-2-furaldehyde

H (10) 13.80%

3-methyl-4-nitrobenzyl

H (11) TBD

Pyrrole H (12) TBD

(13) (14)

(17) (16)

(11) (12)

Figure 3. 1H NMR

data for product (2).

The shift of peaks within the 1H NMR results indicate placement of protons (hydrogen atoms) attached to the substance being analyzed. Data obtained using Bruker400 MHz NMR.