Diketopiperazine-Based, Flexible Tadalafil Analogues: Synthesis, Crystal Structures and Biological Activity Profile

Abstract

Phosphodiesterase 5 (PDE5) is one of the most extensively studied phosphodiesterases that is highly specific for cyclic-GMP hydrolysis. PDE5 became a target for drug development based on its efficacy for treatment of erectile dysfunction. In the present study, we synthesized four novel analogues of the phosphodiesterase type 5 (PDE5) inhibitor—tadalafil, which differs in (i) ligand flexibility (rigid structure of tadalafil vs. conformational flexibility of newly synthesized compounds), (ii) stereochemistry associated with applied amino acid building blocks, and (iii) substitution with bromine atom in the piperonyl moiety. For both the intermediate and final compounds as well as for the parent molecule, we have established the crystal structures and performed a detailed analysis of their structural features. The initial screening of the cytotoxic effect on 16 different human cancer and non-cancer derived cell lines revealed that in most cases, the parent compound exhibited a stronger cytotoxic effect than new derivatives, except for two cell lines: HEK 293T (derived from a normal embryonic kidney, that expresses a mutant version of SV40 large T antigen) and MCF7 (breast adenocarcinoma). Two independent studies on the inhibition of PDE5 activity, based on both pure enzyme assay and modulation of the release of nitric oxide from platelets under the influence of tadalafil and its analogues revealed that, unlike a reference compound that showed strong PDE5 inhibitory activity, the newly obtained compounds did not have a noticeable effect on PDE5 activity in the range of concentrations tested. Finally, we performed an investigation of the toxicological effect of synthesized compounds on Caenorhabditis elegans in the highest applied concentration of 6a,b and 7a,b (160 μM) and did not find any effect that would suggest disturbance to the life cycle of Caenorhabditis elegans. The lack of toxicity observed in Caenorhabditis elegans and enhanced, strengthened selectivity and activity toward the MCF7 cell line made 7a,b good leading structures for further structure activity optimization and makes 7a,b a reasonable starting point for the search of new, selective cytotoxic agents.

Cyclic Dipeptides: The Biological and Structural Landscape with Special Focus on the Anti-Cancer Proline-Based Scaffold

“…DKPs can act as efficient inhibitors of phosphodiesterase-5 (PDE-5) useful in the treatment of sexual/erectile dysfunction [78,283,284] as a revolutionary approach. A wellknown example is tadalafil (and its analogs), which is a highly potent and highly selective drug [79,80,[285][286][287] with limited adverse effects [288] and a prolonged action [289,290]. Notably, tadalafil has the longest half-life of the PDE5 inhibitors.…”

Diketopiperazine Gels: New Horizons from the Self-Assembly of Cyclic Dipeptides

“…The C-C disconnection ( Scheme 1 , C) often involves enolate acylation, albeit radical routes were also described to attain the C-C cyclization [ 63 ]. Despite the various synthetic routes available, the search is still active in this area with new developments pertaining to CDP synthesis appearing also in the most recent literature [ 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 ].…”

Improved HDAC Inhibition, Stronger Cytotoxic Effect and Higher Selectivity against Leukemias and Lymphomas of Novel, Tricyclic Vorinostat Analogues

“…For years, our research group has been working on the design and synthesis of various mono- and polycyclic dilactam derivatives [ 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 ] with potential biological activity. The studies resulted in the discovery of tricyclic benzodiazepines exhibiting selective antileukemic effects [ 92 , 93 , 94 ].…”