Structure‐Based De Novo Design of Non‐nucleoside Adenosine Deaminase Inhibitors.

Abstract

Imidazole derivatives Imidazole derivatives R 0190Structure-Based De Novo Design of Non-nucleoside Adenosine Deaminase Inhibitors. -(TERASAKA*, T.; NAKANISHI, I.; NAKAMURA, K.; EIKYU, Y.; KINOSHITA, T.; NISHIO, N.; SATO, A.; KUNO, M.; SEKI, N.; SAKANE, K.; Bioorg. Med.

Inhibition of adenosine deaminase (ADA)‐mediated metabolism of cordycepin by natural substances

“…To date, several research groups carried out in silico docking study to discover new molecules that bind strongly to the active site of human ADA1. Because small molecules such as adenosine and pentostatin have been known to bind to the active site of ADA1, only these and their derivatives compounds have been used in pharmacophore modeling parameters (Terasaka et al 2003(Terasaka et al , 2005. It should be noted that the secondary structure of naringin is quite bulky compared to that of ADA substrates (adenosine and 2 0 -deoxyadenosine) and known ADA inhibitors (EHNA and pentostatin) ( Fig.…”

Identification of adenosine deaminase inhibitors from Tofu wastewater and litchi peel and their synergistic anticancer and antibacterial activities with cordycepin

“…Genistin and cyanidin‐3‐rutinoside had synergistic anticancer and antimicrobial activities with cordycepin. Unlike the currently used ADA inhibitory compounds coformycin and its analogues which have with toxicity (Terasaka et al ., ), these substances are rich in natural resource and easy to obtained from the food and agriculture industries without toxicity. Furthermore, the utilisation of these wastes not only increases the economic value of related agricultural and food materials, but also reduces environmental pollutants.…”

“…Many ADA inhibitory compounds were synthesised, such as modified coformycin and 2‐deoxycoformycin, 1‐deaza adenosine derivatives (Cristalli et al ., ), 2‐substituted amino pyrazolopyrimidines (Da Settimo et al ., ) and the EHNA [erythro‐9‐ (2‐hydroxyl‐3‐nonyl) adenine compounds (Schaeffer & Schwender, ; Bessodes et al ., ; Antonini et al ., ; Cristalli et al ., ; Vargeese et al ., ; Barankiewicz et al ., ; Curtis et al ., ; Pham et al ., ). However, only pentostatin has been developed as a clinical drug for the treatment of lymphoma and leukaemia diseases, which is still not ideal as its high toxicity and high price (Terasaka et al ., ).…”

Structure-Based Design, Synthesis, and Structure−Activity Relationship Studies of Novel Non-nucleoside Adenosine Deaminase Inhibitors

“…15,16 However, none are used clinically because all are nucleoside analogues or EHNA derivatives and have poor pharmacokinetics, such as rapid metabolism. [17][18][19] We speculated that the unfavorable properties of the known inhibitors could be im- proved by changing the nucleoside framework to a nonnucleoside framework and initiated a search for nonnucleoside ADA inhibitors. 19 Despite the difficulty of converting a nucleoside to non-nucleoside, a recent report from our laboratories has described the discovery of a novel, highly potent non-nucleoside ADA inhibitor 1 (K i ) 7.7 nM to human ADA) (Figure 2).…”

“…[17][18][19] We speculated that the unfavorable properties of the known inhibitors could be im- proved by changing the nucleoside framework to a nonnucleoside framework and initiated a search for nonnucleoside ADA inhibitors. 19 Despite the difficulty of converting a nucleoside to non-nucleoside, a recent report from our laboratories has described the discovery of a novel, highly potent non-nucleoside ADA inhibitor 1 (K i ) 7.7 nM to human ADA) (Figure 2). 20 This compound was discovered by intentional hybridization of two structurally distinct lead compounds [2 (K i ) 5.9 µM) and 3 (K i ) 1.2 µM)] by only two structure-based drug design (SBDD) iterations (Figure 2), and as a result, no detailed information on structure-activity relationships (SAR) for the hybrid compound was available.…”