Retention of Inhibitory Potency of an ACE Inhibitor Conjugated with Rh(III) and Pd(II) (Iminophosphorano)phosphines. Synthesis and X-ray Structural Investigations

Succinimido, amido, and ester functionalized tetrafluoroaryl azides selectively oxidize bisdiphenylphosphinomethane at one of the P(III) centers giving (iminophosphorano)phosphines 6, 7, and 8 respectively in high yields. Succinimido functionalized perfluoroaryl azido (iminophosphorano)phosphine is attached to angiotensin converting enzyme (ACE) inhibitor, lisinopril at one end, leaving the other end for chelation to Rh(III) and Pd(II) precursors including radioactive analogues establishing the hetero-bifunctionality for potential in vivo tracking of the radiotracer. The measurement of inhibitory potency of lisinopril−metal conjugates (Rh and Pd), modified through the primary amine reveals an increase in inhibitory potency, although small, retaining the target potential of native lisinopril toward specific biological sites. However, direct complexation utilizing the carboxylic groups of lisinopril with a Cu precursor resulted in the reduction of inhibitory potency from nM to μM levels rendering it less useful for applications as an ACE inhibitor. Single-crystal X-ray structural investigation of the Rh(III) perfluoroaryl (iminophosphorano)phosphine complex 12 shows a distorted mer octahedral configuration with two ligands per metal center and only one of the phosphiniminato nitrogen atom coordinating to the metal. Pd(II) complex 18 reveals that the metal is bound to the iminato nitrogen atom and the P(III) center via cis disposition to form a five-membered ring. X-ray data for 12:  triclinic, P-1, a = 11.570 (6) Å b = 13.668 Å(7) c = 20.709 (10) Å, α = 86.068 (10), β = 83.774 (10), γ = 83.503 (10) V = 3229.6 (3) ų, Z = 2, R = 0.028, R_w = 0.050. X-ray data for 18:  triclinic, P-1, a = 11.457 (3) Å, b = 12.223 (3) Å, c = 13.219 (4) Å, α = 89.98 (20), β = 73.710 (20), γ = 69.980 (20), V = 1665.7 (8) ų, Z = 2, R = 0.024, R_w = 0.031.