ABSTRACT
The development of targeted chemotherapeutic agents against colorectal cancer (CRC), one of the most common cancers with a high mortality rate, is in a constant need. Nannocystins are a family of myxobacterial secondary metabolites featuring a 21-membered depsipeptide ring. The in vitro anti-CRC activity of natural and synthetic nannocystins was well documented, but little is known about their in vivo efficacy and if positive, the underlying mechanism of action. In this study we synthesized a nitroaromatic nannocystin through improved preparation of a key fragment, and characterized its in vitro activity and in vivo efficacy against CRC. We first described the total synthesis of compounds 2-4 featuring Heck macrocyclization to forge their 21-membered macrocycle. In a panel of 7 cancer cell lines from different tissues, compound 4 inhibited the cell viability with IC values of 1-6 nM. In particular, compound 4 (1, 2, 4 nM) inhibited the proliferation of CRC cell lines (HCT8, HCT116 and LoVo) in both concentration and time dependent manners. Furthermore, compound 4 concentration-dependently inhibited the colony formation and migration of CRC cell lines. Moreover, compound 4 induced cell cycle arrest at sub-G1 phase, apoptosis and cellular senescence in CRC cell lines. In three patient-derived CRC organoids, compound 4 inhibited the PDO with IC values of 3.68, 28.93 and 11.81 nM, respectively. In a patient-derived xenograft mouse model, injection of compound 4 (4, 8 mg/kg, i.p.) every other day for 12 times dose-dependently inhibited the tumor growth without significant change in body weight. We conducted RNA-sequencing, molecular docking and cellular thermal shift assay to elucidate the anti-CRC mechanisms of compound 4, and revealed that it exerted its anti-CRC effect at least in part by targeting AKT1.
Subject(s)
Antineoplastic Agents , Cell Proliferation , Colorectal Neoplasms , Depsipeptides , Macrocyclic Compounds , Proto-Oncogene Proteins c-akt , Animals , Humans , Mice , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/pathology , Colorectal Neoplasms/metabolism , Depsipeptides/pharmacology , Depsipeptides/therapeutic use , Depsipeptides/chemistry , Depsipeptides/chemical synthesis , Drug Discovery , Drug Screening Assays, Antitumor , Proto-Oncogene Proteins c-akt/metabolism , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
Alzheimer's disease (AD) is a degenerative disease of the nervous system. Compound I reported to have inhibitory activity on AChE was used as a lead compound in this study, and 4-pyridinylthiazole-2-amines were designed by optimizing compound I structure. The new compounds were synthesized from acetylpyridines through five-steps of reaction, and their inhibition activities on AChE were measured in vitro by Ellman method. The new compounds exhibited a clear inhibitory activity on AChE in vitro. The bioactivity of compound 13c was the best among them, and its IC(50) value was 0.15 µmol·L(-1), which was better than that of rivastigmine and compound I in the control. Meanwhile, it exhibited little inhibition on butyrylcholinesterase. So the selective inhibitory activities of 4-pyridinylthiazole-2-amines to acetylcholinesterase were worth of studying furtherly.
Subject(s)
Amines/pharmacology , Cholinesterase Inhibitors/pharmacology , Drug Design , Acetylcholinesterase , Alzheimer Disease , Amines/chemical synthesis , Butyrylcholinesterase , Cholinesterase Inhibitors/chemical synthesis , Rivastigmine , Structure-Activity RelationshipABSTRACT
In this paper, fourteen new L-proline derivatives were designed and synthesized, and their acetlcholinesterase (AChE) inhibitory activities were also investigated in vitro. New L-proline derivatives were prepared from substituted 2-bromo-1-acetophenones through four-step reaction; and their bioactivities as AChE inhibitors were measured by Ellman spectrophotometry. The results showed that the target compounds had a certain AChE inhibitory activity to in vitro. The bioactivity of compound 8b was the best of them, and its IC50 value was 5.45 µmol.L-1, which was better than that of rivastigmine. So the acetylcholinesterase inhibitory activities of new L-proline derivatives were worth to be further studied.
Subject(s)
Cholinesterase Inhibitors/chemical synthesis , Drug Design , Proline/analogs & derivatives , Acetylcholinesterase , Cholinesterase Inhibitors/chemistry , Rivastigmine/chemistry , Structure-Activity RelationshipABSTRACT
The target compounds were prepared from 5-aminobenzimidazolone by two steps reaction, and their AChE inhibitory activities were measured by Ellman method in vitro. The AChE inhibitory activity of compound 4d is the best of them, and its IC50 value is equal to 7.2 µmol·L(-1), which is better than that of rivastigmine; moreover the 4d had no inhibitory activities to BuChE. Therefore, the inhibitory activities of 5-aminobenzimidazolone derivatives to acetylcholinesterase are worth further researching.
