Development of a New Benzophenone–Diketopiperazine-Type Potent Antimicrotubule Agent Possessing a 2-Pyridine Structure

Abstract

A new benzophenone-diketopiperazine-type potent antimicrotubule agent was developed by modifying the structure of the clinical candidate plinabulin (1). Although the right-hand imidazole ring with a branched alkyl chain at the 5-position in 1 was critical for the potency of the antimicrotubule activity, we successfully substituted this moiety with a simpler 2-pyridyl structure by converting the left-hand ring from a phenyl to a benzophenone structure without decreasing the potency. The resultant compound 6b (KPU-300) exhibited a potent cytotoxicity, with an IC50 value of 7.0 nM against HT-29 cells, by strongly binding to tubulin (K d = 1.3 μM) and inducing microtubule depolymerization.

Pyridine Based Antitumour Compounds Acting at the Colchicine Site

“…21) in the late nineties, [180][181][182][183] the diketopyperazines (DKP) have been developed as a new family of antitubulin agents, binding at the colchicine site. These compounds are moderately potent in comparison with reference combretastatin A-4 (5), but recently the coupling of the benzophenone [184] moiety to the DKP has increased the potency of these compounds and the structure activity relationships demonstrated that a 2-pyridyl ring bonded to the DKP is highly convenient for the activity (78). The benzophenone can also be replaced by a pyridine.…”

Biological activity and interaction mechanism of the diketopiperazine derivatives as tubulin polymerization inhibitors

“…16 For structure-activity relationship study, a series of diketopiperazine (DKP) derivatives were synthesized and their biological activities were evaluated. 17,18 Notably, there was a correlation between the dissociation constants of the inhibitors binding to tubulin (K d ) and the IC 50 values against human colon cancer cell lines HT-29. 17,18 For further rational drug design, seven DKP derivatives including plinabulin were synthesized (Fig.…”

“…17,18 Notably, there was a correlation between the dissociation constants of the inhibitors binding to tubulin (K d ) and the IC 50 values against human colon cancer cell lines HT-29. 17,18 For further rational drug design, seven DKP derivatives including plinabulin were synthesized (Fig. 2), and their antiproliferative activities were evaluated against human pancreatic cancer cell line BxPC-3 and human lung cancer cell line NCI-H460.…”

Feasibility study on the reaction of 1,4-diazabicyclo[2.2.2]octane (DABCO) with (L-Serine-L-Serine) and (L-Phenylalanine-L-Serine) diketopiperazines

“…2,5-diketopiperazines (DKP's), such as compounds (1) and (3), have potential to serve as building blocks for important class of compounds. [1][2][3][4][5][6][7][8][9] The presence of these 2,5-DKP's in bioactive natural products, their synthetic utility and applications in medicinal chemistry is excellently reviewed by Borthwick. 10 A detailed description of the application of these 2,5-DKP's in peptide and combinatorial chemistry is thoroughly reviewed by P.M. Fischer.…”

“…11 2,5-DKP's have continued to establish impact on the frontiers of organic, structural, and medicinal chemistry. 12 DKP derivatives, such as enol di-tosylate (2) and enol tosylate (4), can serve as building blocks for a class of important compounds called endiamino peptides [compounds bearing a 1,3-diaminoethenyl functional group]. 13 Endiamino bonds can induce a conformational rigidity in peptides and hydrogen bonding assisted enzyme sulfatases catalysis.…”