Identification of candidate molecular targets of the novel antineoplastic antimitotic NP-10

Abstract

We previously reported the identification of a novel antimitotic agent with carbazole and benzohydrazide structures: N′-[(9-ethyl-9H-carbazol-3-yl)methylene]-2-iodobenzohydrazide (code number NP-10). However, the mechanism(s) underlying the cancer cell-selective inhibition of mitotic progression by NP-10 remains unclear. Here, we identified NP-10-interacting proteins by affinity purification from HeLa cell lysates using NP-10-immobilized beads followed by mass spectrometry. The results showed that several mitosis-associated factors specifically bind to active NP-10, but not to an inactive NP-10 derivative. Among them, NUP155 and importin β may be involved in NP-10-mediated mitotic arrest. Because NP-10 did not show antitumor activity in vivo in a previous study, we synthesized 19 NP-10 derivatives to identify more effective NP-10-related compounds. HMI83-2, an NP-10-related compound with a Cl moiety, inhibited HCT116 cell tumor formation in nude mice without significant loss of body weight, suggesting that HMI83-2 is a promising lead compound for the development of novel antimitotic agents.

SLX4–XPF mediates DNA damage responses to replication stress induced by DNA–protein interactions

“…Cell-cycle analysis was performed essentially as described previously ( Yokoyama et al, 2019 ; Sugimoto et al, 2011 ). For the experiments shown in Fig.…”

Heteroglycoclusters through Unprecedented Orthogonal Chemistry Based on N‐Alkylation of N‐Acylhydrazone

“…[47] Starting from NAH B or C, alkylation should give not only N-alkylation leading to targeted N-Alk-NAH D key intermediate, but also to O-alkylation, leading to O-Alk-NAH E in a mixture usually observed with amide analogs. [16,30] D is a valuable and unprecedented intermediate for subsequent click chemistry orthogonal reaction to reach heterodisaccharide and heteroglycoclusters. Below we address various cases with a special focus on examples involving carbohydrate derivatives widespread in glycans of antigens and host cells.…”

“…Although the NAH function could exist under Z C=N and E C=N π‐diastereoisomers via condensation of an acylhydrazide and aldehyde, the steric hindrance led widely to E C=N configuration [47] . Starting from NAH B or C , alkylation should give not only N ‐alkylation leading to targeted N ‐Alk‐NAH D key intermediate, but also to O ‐alkylation, leading to O ‐Alk‐NAH E in a mixture usually observed with amide analogs [16,30] . D is a valuable and unprecedented intermediate for subsequent click chemistry orthogonal reaction to reach heterodisaccharide and heteroglycoclusters.…”

“…This N-substituted imine, [40] or amide-imine dual function [41] is more stable than its unfunctionalized analog and has had numerous applications such as DCC, [28,42] supramolecular self-assembly, [40,43] aza-Diels-Alder cyclization, [44] iodine-catalyzed oxidative cyclization, [45] asymmetric C-alkylation, [29] or a rare NAH-N-alkylation widely used as a conformational lock. [30,46,47] Strangely, the latter remains unexploited as a key step in orthogonal synthesis which led to our present investigation. Here we report the unprecedented highly efficient and widely applicable orthogonal strategy exemplified in the synthesis of a library of aromatic small molecule N-alk-NAH glycoconjugates.…”

“…[7,26,27] N-acylhydrazone (NAH) is a popular function that enjoys significant attention in organic and biomaterial chemistries thanks to its dynamic covalent bond [28] and its use as an intermediate in miscellaneous reactions. [29,30] Its role in medicinal chemistry, due to its recognition by many receptors behind a broad range of biological activities [31] and drug delivery, [28] is also well documented. However, the use of NAH in glycoconjugate synthesis remains limited.…”