4-Fluorinatedl-lysine analogs as selective i-NOS inhibitors: methodology for introducing fluorine into the lysine side chain

Abstract

In the literature, the introduction of fluorine into bioactive molecules has been known to enhance the biological activity relative to the parent molecule. Described in this article is the synthesis of 4R-fluoro-L-NIL (12) and 4,4-difluoro-L-NIL (23) as part of our iNOS program. Both 12 and 23 were found to be selective iNOS inhibitors as shown in Table 2 below. Secondarily, methodology to synthesize orthogonally protected 4-fluoro-L-lysine and 4,4-difluoro-L-lysine has been developed.

Detailed insights from microarray and crystallographic studies into carbohydrate recognition by microneme protein 1 (MIC1) of Toxoplasma gondii

“…While a fluorine atom retains the ability to accept a hydrogen bond, the effects of its increased electronegativity are not straightforward. In four examples out of 18 from the PDB the fluorine acts as a hydrogen bond donor 23, 36, 37. More striking evidence for CF…HO hydrogen bonding can be found in the 3′SiaLacNAc 1–4 structures.…”

“…Weighted 2| F o | − | F c | electron density maps of (a) 2′F‐3′SiaLacNAc 1–4 , (b) 3′SiaLacNAc 1–3 and (c) 2′F‐3′SiaLacNAc 1–3 , contoured at 1.0 r.m.s. (d) Overlay of all six TgMIC1‐MARR crystal structures: no ligand (magenta; pdb:http://firstglance.jmol.org/fg.htm?mol=2Jh1,23 3′SiaLacNAc 1–4 soak (yellow; pdb:http://firstglance.jmol.org/fg.htm?mol=2Jhd), 2′F‐3′SiaLacNAc 1–4 soak (green; pdb:http://firstglance.jmol.org/fg.htm?mol=3f53), 3′SiaLacNAc 1–3 soak (red; pdb:http://firstglance.jmol.org/fg.htm?mol=3f5a), 2′F‐3′SiaLacNAc 1–3 soak (blue; pdb:http://firstglance.jmol.org/fg.htm?mol=3f5e) and.6′SiaLacNAc 1–4 soak (cyan; pdb:http://firstglance.jmol.org/fg.htm?mol=2Jh7). Disulphide bridges are shown as black sticks and the N and C‐termini are labeled.…”

Selective Neuronal Nitric Oxide Synthase Inhibitors

“…The corresponding guanidines, rather than amidines, show no isozyme selectivity (the guanidine analogue of 41 is a poor substrate and of 42 is a weak mixed inhibitor). Incorporation of one or two fluorines at C-4 or C-5 of L-NIL gives iNOS-selective inhibitors [104,105] Replacement of one of the side chain methylenes of L-NIL and homo-NIL (one more methylene in the side chain than L-NIL) with an oxygen, sulfur, sulfoxide, and sulfone gives a series of acetamidine derivatives of L-NIL that are even more iNOS selective than L-NIL [106]. Introduction of a 2,2,2-trifluoroethyl group at the C-6 position of L-NIL or Llysine gives compounds with no inhibitory activity [107].…”

A convenient AIBN-initiated radical addition of ethyl iododifluoroacetate to alkenes

“…30%) to afford a colourless oil (282 mg, 69%). 19 4.23 (1H,dtd,J = 9.0,7.0,4.5 Hz),3.65 (2H,t,J = 6.5 Hz),2.92 (1H,dtd,J = 18.5,15.5,6.5 Hz),2.74 (1H,dddd,J = 18.0,15.5,12.5,7.0 Hz), 1.87-1.69 and 1.61-1.29 (15H, m), 1.38 (3H, t, J = 7.0 Hz); 13 C NMR (100 MHz, CDCl 3 ) 163. 6 (t,J = 32.5 Hz),115.3 (t,J = 251.5 Hz),63.4,63.1,45.5 (t,J = 23.0 Hz),32.9,29.6,29.4,28.6,25.8,23.4 (t,J = 3.5 Hz),14.3.…”

“…This is typically achieved by a 2-step Barton-McCombie reduction process [6] via a thiocarbamate [7] or a thiocarbonate [8] derivative. Alternatively, a radical-mediated addition reaction using 1a,b leads to adducts 2a or 2b, with subsequent reduction of the halide required to obtain 3.…”