Tight binding enantiomers of pre-clinical drug candidates

Abstract

MTDIA is a picomolar transition state analogue inhibitor of human methylthioadenosine phosphorylase and a femtomolar inhibitor of Escherichia coli methylthioadenosine nucleosidase. MTDIA has proven to be a non-toxic, orally available pre-clinical drug candidate with remarkable anti-tumour activity against a variety of human cancers in mouse xenografts. The structurally similar compound MTDIH is a potent inhibitor of human and malarial purine nucleoside phosphorylase (PNP) as well as the newly discovered enzyme, methylthioinosine phosphorylase, isolated from Pseudomonas aeruginosa. Since the enantiomers of some pharmaceuticals have revealed surprising biological activities, the enantiomers of MTDIH and MTDIA, compounds 1 and 2, respectively, were prepared and their enzyme binding properties studied. Despite binding less tightly to their target enzymes than their enantiomers compounds 1 and 2 are nanomolar inhibitors.

Keywords: Cancer; Drug; Enantiomer; Enzyme; Transition state analogue.

Figure 1

Figure 2

Figure 3

EcMTAN bound to (3S,4R)-MTDIA (left) and (3R,4S)-MTDIA (right). The key residues are shown as sticks. The nearby residues are shown as lines.

Scheme 1

(a) Novozyme 435, H₂O, acetone, pH 7.5, 27 °C, reflux; (b) BF₃.OEt₂, NaBH₄, THF, 0 °C → room temperature; (c) Pd(OH)₂, H₂, conc NH₄OH, MeOH, room temperature; (d) Boc₂O, MeOH, room temperature; (e) MsCl, Hunig's base, CH₂Cl₂, −60 ଌ (f) NaSMe, DMF, room temperature; (g) MeOH; conc HCl, room temperature.

Scheme 2

(a) Aminoacetonitrile bisulfate, NaOAc, MeOH, room temperature; (b) Methyl chloroformate, Et₃N, CH₂Cl₂, room temperature; (c) CH₂Cl₂, DBU, MeOH, room temperature; (d) Formamidine acetate, EtOH, reflux; (e) KOH, H₂O, reflux.

Scheme 3

(a) aq Formaldehyde, NaOAc, 1,4-dioxane, H₂O, 95 °C