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cis-2-Aminocyclohexylcarbamoylphosphonic acid ( cis-ACCP) was evaluated in vitro and in two in vivo cancer metastasis models. It reduced metastasis formation in mice by approximately 90% when administered by a repetitive once daily dosing regimen of 50 mg/kg via oral or intraperitoneal routes and was nontoxic up to 500 mg/kg, following intraperitoneal administration daily for two weeks. Pharmacokinetic investigation of cis-ACCP in rats revealed distribution restricted into the extracellular fluid, which is the site of action for the antimetastatic activity and rapid elimination ( t 1/2 approximately 19 min) from blood. Sustained and prolonged absorption ( t 1/2 approximately 126 min) occurred via paracellular mechanism along the small and large intestine with overall bioavailability of 0.3%. The in vivo concentrations of cis-ACCP in the blood in rats was above the minimal concentration for antimetastatic/MMP-inhibitory activity, thus explaining the prolonged action following once daily administration. Finally, 84% of the intravenously administered cis-ACCP to rats was excreted intact in the urine.

Seven 4-phenoxybenzenesulfonamidopolymethylene carbamoylphosphonates (CPOs) bearing two to eight methylene units in the polymethylene chain were synthesized and evaluated as matrix metalloproteinase (MMP) inhibitors. The five lowest homologues [(CH₂)₂-₆] are selective MMP-2 inhibitors, whereas the two with the longest linkers [(CH₂)₇,₈] lack inhibitory activity. The most potent homologues are those with (CH₂)₅,₆; these two were evaluated for antimetastatic activity in a murine melanoma model and showed good potency both by oral and intraperitoneal administration without any toxic--including musculoskeletal--side effects. In contrast to the previously reported cis-ACCP, which was shown to inhibit MMP-2 for ∼30 min, the new compounds inhibit MMP activity for the duration of measurement, lasting several hours. Pharmacokinetic evaluation revealed, on the one hand, low oral bioavailability; on the other hand, a relatively large calculated volume of distribution, consistent with the observed reversible absorption of CPO 5 to hydroxyapatite, as a model for bone.

018. Figure 4 depicts a recently obtained cocrystal structure (PDB code 2ONC).

Autotaxin is an extracellular, two zinc-centered enzyme that hydrolyzes lysophosphatidyl choline to lysophosphatidic acid, involved in various cancerous processes, e.g. migration, proliferation and tumor progression. We examined the autotaxin inhibitory properties of extended structure carbamoylphosphonates (CPOs) PhOC 6 H 4 SO 2 NH(CH 2 ) n NHCOPO 3 H 2 , with increasing lengths of methylene chains, (CH 2 ) n , n ¼ 4-8. Carbamoylphosphonates having n ¼ 6, 7, 8 inhibited autotaxin in vitro with IC 50 & 1.5 mM. Using an imaging probe we demonstrated that compound n ¼ 6 inhibits recombinant autotaxin activity in vitro and in vivo, following oral CPO administration. Additionally, daily oral administration of compound n ¼ 7 inhibited over 90% of lung metastases in a murine melanoma metastasis model. Both the carbamoylphosphonates and the enzymes reside and interact in the extracellular space expecting minimal toxic side effects, and presenting a novel approach for inhibiting tumor proliferation and metastasis dissemination.

No abstract

Carbamoylphosphonates (CPOs) have recently been identified as extracellular in vivo active inhibitors of the cancer and metastasis‐promoting extracellular enzymes, carbonic anhydrases (CAs) IX and XII, and matrix metalloproteinase‐2 (MMP‐2). This article describes the stereoselective synthesis and the evaluation of the biological properties of a pair of enantiomeric aminoalkylcarbamoylphosphonates, which have been enantioselectively synthesized from l‐serine, using functional group‐transformations. The structures of the enantiomeric products have been determined by X‐ray crystallography. The enantiomeric purities of compounds have been confirmed by chiral shift reagent NMR experiments and by circular dichroism. In vitro evaluation of the CPOs synthesized revealed that they possess micromolar IC50 inhibitory action against CAIX and CAXII. The two enantiomers as well as the racemic or optically inactive ones do not differ by any significant extent from previously reported CPOs’ CA inhibitory values. On the other hand, MMPs inhibitory activities are rather weak; only MMP‐2 showed a notable IC50 value.