Replacement of imidazolyl by pyridyl in biphenylmethylenes results in selective CYP17 and dual CYP17/CYP11B1 inhibitors for the treatment of prostate cancer.

Androgens are well-known to stimulate prostate cancer (PC) growth. Thus, blockade of androgen production in testes and adrenals by CYP17 inhibition is a promising strategy for the treatment of PC. Moreover, many PC patients suffer from glucocorticoid overproduction, and importantly mutated androgen receptors can be stimulated by glucocorticoids.

Isopropylidene substitution increases activity and selectivity of biphenylmethylene 4-pyridine type CYP17 inhibitors.

CYP17 inhibition is a promising therapy for prostate cancer (PC) because proliferation of 80% of PC depends on androgen stimulation. Introduction of isopropylidene substituents onto the linker of biphenylmethylene 4-pyridines resulted in several strong CYP17 inhibitors, which were more potent and selective, regarding CYP 11B1, 11B2, 19 and 3A4, than the drug candidate abiraterone.

First syntheses of melophlins P, Q, and R, and effects of melophlins on the growth of microorganisms and tumor cells.

The marine tetramic acid (=1,5-dihydro-4-hydroxy-2H-pyrrol-2-ones) derivatives melophlin P, Q, and R (1p-1r, resp.) were synthesized for the first time in only four steps. Together with the congenerous melophlins A-C and G, they were also tested for antimicrobial and cytotoxic effects.

Metal complexes of natural melophlins and their cytotoxic and antibiotic activities.

Complexes of the natural melophlins A and C with Mg, Zn, Ga, La and Ru were prepared, characterized and tested for antimicrobial and cytotoxic effects. The lanthanum complex La(melophlinato C)(3) and the ruthenium complex chlorido(eta(6)-p-cymene)(melophlinato C)ruthenium(II) inhibited cells of human A-498 kidney cancer at IC(50)=0.54 microM and 1.

CYP17 inhibitors. Annulations of additional rings in methylene imidazole substituted biphenyls: synthesis, biological evaluation and molecular modelling.

Twenty-one novel compounds originating from two classes of annulated biphenyls were synthesized as mimetics of the steroidal A- and C-rings and examined for their potency as inhibitors of human CYP17. Selected compounds were tested for inhibition of the hepatic CYP enzyme 3A4. Potent CYP17 inhibitors were found for each class, compound 9 (17 and 71% at 0.

Synthesis, biological evaluation, and molecular modeling of abiraterone analogues: novel CYP17 inhibitors for the treatment of prostate cancer.

Abiraterone, a steroidal cytochrome P450 17alpha-hydroxylase-17,20-lyase inhibitor (CYP17), is currently undergoing phase II clinical trials as a potential drug for the treatment of androgen-dependent prostate cancer. Since steroidal compounds often show side effects attributable to their structure, we have tried to replace the sterane scaffold by nonsteroidal core structures. The design and synthesis of 20 new abiraterone mimetics are described.

Synthesis, biological evaluation and molecular modelling studies of methyleneimidazole substituted biaryls as inhibitors of human 17alpha-hydroxylase-17,20-lyase (CYP17). Part I: Heterocyclic modifications of the core structure.

Novel chemical entities were prepared via Suzuki and S(N) reaction as AC-ring substrate mimetics of CYP17. The synthesised compounds 1-31 were tested for activity using human CYP17 expressed in Escherichia coli. Promising compounds were tested for selectivity against hepatic CYP enzymes (3A4, 2D6, 1A2, 2C9, 2C19, 2B6).

Synthesis, biological evaluation and molecular modelling studies of novel ACD- and ABD-ring steroidomimetics as inhibitors of CYP17.

Two novel classes of non-steroidal substrate mimetics were synthesised and examined for their potency as inhibitors of human CYP17. Selected compounds were tested for inhibition of hepatic CYP enzymes 3A4, 1A2, 2C9 and 2C19. The most promising compound 15 showed a good inhibition of the target enzyme (31% and 66% at 0.

Solution-phase and solid-phase syntheses of enzyme inhibitor RK-682 and antibiotic agglomerins.

The enzyme inhibitor RK-682 (5R)-(+)-1 was prepared in solution and on a solid support from (2R)-glycerates in five steps and ca. 40% overall yield. Key steps were a ring-closing tandem addition-Wittig alkenation reaction of the respective protected or immobilized glycerates with the ylide Ph(3)PCCO and the 3-acylation of the tetronic acids thus obtained with palmitic acid.

Synthesis and reactions of polymer-bound Ph3P=C=C=O: a quick route to tenuazonic acid and other optically pure 5-substituted tetramates.

Polystyrene-bound cumulated ylide Ph3PCCO was prepared on a large scale in two steps. It reacts with Grignard compounds, amines and alcohols to give immobilized acyl, amide and ester ylides, respectively. Their Wittig reactions lead to alkenes free of phosphane oxide.