Synthesis and Structure–Activity Relationship Study of Antimicrotubule Agents Phenylahistin Derivatives with a Didehydropiperazine-2,5-dione Structure

Abstract

Plinabulin (11, NPI-2358) is a potent microtubule-targeting agent derived from the natural diketopiperazine "phenylahistin" (1) with a colchicine-like tubulin depolymerization activity. Compound 11 was recently developed as VDA and is now under phase II clinical trials as an anticancer drug. To develop more potent antimicrotubule and cytotoxic derivatives based on the didehydro-DKP skeleton, we performed further modification on the tert-butyl or phenyl groups of 11, and evaluated their cytotoxic and tubulin-binding activities. In the SAR study, we developed more potent derivatives 33 with 2,5-difluorophenyl and 50 with a benzophenone in place of the phenyl group. The anti-HuVEC activity of 33 and 50 exhibited a lowest effective concentration of 2 and 1 nM for microtubule depolymerization, respectively. The values of 33 and 50 were 5 and 10 times more potent than that of CA-4, respectively. These derivatives could be a valuable second-generation derivative with both vascular disrupting and cytotoxic activities.

Isomethoxyneihumicin, a new cytotoxic agent produced by marine Nocardiopsis alba KM6-1

“…The diketopiperazines inhibited the cell cycle at the G2/M phase by inhibiting tubulin polymerization. 15 Its tert-butyl derivative, named plinabulin 16 was entered into a phase III clinical trial for the treatment of advanced metastatic non-small cell lung cancer in 2015. 17 Isomethoxyneihumicin has a diketopiperazinelike core skeleton.…”

“…This biological characteristic appeared to be similar to those of halimide 13 and plinabulin. 16 Unfortunately, the compound showed no activity against HCT116 cells, HaCaT cells or CHO cells, at least Isomethoxyneihumicin is a mixture of lactam-lactim tautomers 1 and 2 at a ratio of 2:1 in DMSO-d 6 . Although methoxyneihumicin (3) was previously reported to form a single structure, we found that it is also a mixture of lactam-lactim tautomers at a ratio of 5:1 in DMSO-d 6 (data not shown).…”

Bulky α,β-dehydroamino acids: their occurrence in nature, synthesis, and applications

“…51 Structureeactivity studies have shown that the potency of 23 can be further increased by attaching fluoro or benzoyl groups to the phenyl moiety. 52 Several DTrp-containing natural products have been discovered, but in light of the recent review in this area 2d only selected examples with interesting structures and/or potent bioactivity will be discussed herein. In 1958, Misiek et al isolated telomycin (24, Fig.…”

Medicinal Chemistry and Chemical Biology of Diketopiperazine-Type Antimicrotubule and Vascular-Disrupting Agents

“…19,20) We first established a convenient synthetic route to compound 7 that would allow for the synthesis of a variety of derivatives. Compound 7 was synthesized from pivalic anhydride 8a in six steps (Chart 1).…”

“…Plinabulin (7) exhibited potent antitumor activity 19) and an interesting binding mode [36][37][38] ; however, its low water solubility (<0.1 µg/mL) needed to be improved to increase its pharmaceutical value. Compound 7 is currently injected in combination with a solubilizing agent that can induce hypersensitivity in the context of long-term administration.…”