ABSTRACT
Here, a series of 3-(6-aminopyridin-3-yl) benzamide derivatives were designed and synthesized. Cell viability assay indicated that most compounds exhibited potent antiproliferative activity against all the tested cancer cells. Among them, compound 7l displayed the best antiproliferative activity particularly in A549 cells, with an IC50 value of 0.04 ± 0.01 µM. RNA-seq analysis was employed to explore the potential pathways related to the antiproliferative activity of compound 7l. The data revealed that 7l exerted antiproliferative activity mainly by regulating cell cycle, DNA replication and p53 signaling pathway. Indeed, compound 7l induced G2/M phase arrest by AURKB transcription inhibition and resulted in cell apoptosis via p53 signaling pathway. Most importantly, compound 7l demonstrated potent antitumor activity in A549 xenograft tumor model. Collectively, 7l might be a promising lead compound for the development of new therapeutic agents for AURKB overexpressed or mutated cancers.
Subject(s)
Antineoplastic Agents , Apoptosis , Benzamides , Cell Cycle Checkpoints , Cell Proliferation , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Benzamides/pharmacology , Benzamides/chemical synthesis , Benzamides/chemistry , Cell Proliferation/drug effects , Structure-Activity Relationship , Molecular Structure , Cell Cycle Checkpoints/drug effects , Animals , Mice , Mice, Nude , Cell Line, Tumor , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Transcription, Genetic/drug effects , Mice, Inbred BALB CABSTRACT
A small number of primate species including snub-nosed monkeys (colobines), geladas (papionins) and humans live in multilevel societies (MLSs), in which multiple one-male polygamous units (OMUs) coexist to form a band, and non-breeding males associate in bachelor groups. Phylogenetic reconstructions indicate that the papionin MLS appears to have evolved through internal fissioning of large mixed-sex groups, whereas the colobine MLS evolved through the aggregation of small, isolated OMUs. However, how agonistic males maintain tolerance under intensive competition over limited breeding opportunities remains unclear. Using a combination of behavioural analysis, satellite telemetry and genetic data, we quantified the social network of males in a bachelor group of golden snub-nosed monkeys. The results show a strong effect of kinship on social bonds among bachelors. Their interactions ranged from cooperation to agonism, and were regulated by access to mating partners. We suggest that an 'arms race' between breeding males' collective defence against usurpation attempts by bachelor males and bachelor males' aggregative offence to obtain reproductive opportunities has selected for larger group size on both sides. The results provide insight into the role that kin selection plays in shaping inter-male cohesion which facilities the evolution of multilevel societies. These findings have implications for understanding human social evolution, as male-male bonds are a hallmark of small- and large-scale human societies.
Subject(s)
Breeding , Colobinae/physiology , Cooperative Behavior , Sexual Behavior, Animal , Animals , Colobinae/genetics , Male , Phylogeny , TelemetryABSTRACT
Since reconciliation was first described more than 20 years ago, a large number of postconflict behaviors have been observed among females in many polygynous primate species. However, few studies have been conducted among males, perhaps due to the rarity with which they maintain friendly relationships with one another and their aggressive competition for resources. Although this is true for many primate males, Sichuan snub-nosed monkeys Rhinopithecus roxellana represent a potential exception as male cooperation has been known to occur. In this study, using postconflict/matched-control(PC-MC) and time-rule methods, we analyzed postconflict behavior among males and the possible occurrence of bystander affiliation or reconciliation. A total of 246 PC-MC pairs among leader males were obtained. On average, each leader male exhibited only 0.04 aggressive behaviors per observation hour, and conciliation among leader males occurred at a low rate (2.03%) relative to other primate species. The occurrence of consolation-affiliation interactions between focal males and group members other than former opponents differed significantly between PCs and MCs, which is the first time this has been confirmed among R. roxellana males. We discuss the results in light of recent theories concerning consolation in primates. The patterns of postconflict contact demonstrated that R. roxellana may be a unique species among colobines.