EB1627: a soluble prodrug of the potent anticancer cyanoguanidine CHS828.

To overcome pharmacokinetic and solubility problems observed in early clinical trials with the potent anticancer compound CHS828, we synthesised a series of prodrugs with improved properties. The best compound obtained was EB1627, with a tetraethyleneglycol moiety attached to the parent drug via a carbonate linkage. This compound was found soluble enough to be given i.

Synthesis of novel hapten derivatives of 1alpha,25-dihydroxy-vitamin D3 and its 20-epi analogue.

Hapten derivatives of 1alpha,25-dihydroxyvitamin D(3) and its 20-epimer were synthesized and conjugated to a carrier protein for raising polyclonal antibodies. The haptens were linked through spacers at C-16, thereby exposing both the A-ring and the side chain of the molecules, to maximize antibody specificity. The spacers were introduced via stereoselective hydroboration of 16-ene intermediates as the key step.

The synthesis of [26,27-11C]dihydroxyvitamin D(3), a tracer for positron emission tomography (PET).

1Alpha,25-dihydroxyvitamin D(3), an endogenous ligand with the highest affinity for the vitamin D receptor (VDR), was labeled with 11C for use in biological experiments. The radionuclide was incorporated via the reaction of [11C]methyllithium on a methyl ketone precursor in tetrahydrofuran at -10 degrees C. Deprotection of the labeled intermediate yielded 2.

Polyclonal antibodies to EB1089 (seocalcitol), an analog of 1alpha,25-dihydroxyvitamin D(3)*.

A hapten derivative of EB1089 [1(R),3(S),25-trihydroxy-26,27-dimethyl-9,10-seco-24-homocholesta-5(Z),7(E),10(19),22(E),24(E)-pentaene], a side-chain analog of 1alpha,25-dihydroxyvitamin D(3), was synthesized for raising antibodies with a high specificity for EB1089. The A-ring moiety of EB1089 was replaced in the hapten by a linker for conjugation to a protein. Three polyclonal antibodies were obtained by immunizing rabbits with a BSA-conjugate of the hapten.

Examination of structurally selective derivatization of vitamin D(3) analogues by electrospray mass spectrometry.

The structural specificity of vitamin D derivatization by PTAD (4-phenyl-1,2,4-triazoline-3,5-dione) was probed using synthetic analogues and ion trap mass spectrometry. EB 1089, a vitamin D(3) analogue which contains a second site for Diels--Alder cycloaddition on its side-chain, allowed the examination of derivatization modes and comparisons of ion fragment structures. The origins of a PTAD-vitamin D(3) ion fragment, commonly used in metabolite characterization and quantitation of vitamin D(3) analogues (m/z 314), were established; ion trap mass spectrometry revealed that the PTAD comprises a portion of this diagnostic fragment, and is not lost by a retro-Diels--Alder step.