Synthesis and evaluation of new compounds bearing 3-(4-aminopiperidin-1-yl)methyl magnolol scaffold as anticancer agents for the treatment of non-small cell lung cancer via targeting autophagy.

Magnolol and honokiol are the two major active ingredients with similar structure and anticancer activity from traditional Chinese medicine Magnolia officinalis, and honokiol is now in a phase I clinical trial (CTR20170822) for advanced non-small cell lung cancer (NSCLC). In search of potent lead compounds with better activity, our previous study has demonstrated that magnolol derivative C2, 3-(4-aminopiperidin-1-yl)methyl magnolol, has better activity than honokiol. Here, based on the core of 3-(4-aminopiperidin-1-yl)methyl magnolol, we synthesized fifty-one magnolol derivatives. Among them, compound 30 exhibited the most potent antiproliferative activities on H460, HCC827, H1975 cell lines with the IC50 values of 0.63-0.93 µM, which were approximately 10- and 100-fold more potent than those of C2 and magnolol, respectively. Besides, oral administration of 30 and C2 on an H460 xenograft model also demonstrated that 30 has better activity than C2. Mechanism study revealed that 30 induced G0/G1 phase cell cycle arrest, apoptosis and autophagy in cancer cells. Moreover, blocking autophagy by the autophagic inhibitor enhanced the anticancer activity of 30in vitro and in vivo, suggesting autophagy played a cytoprotective role on 30-induced cancer cell death. Taken together, our study implied that compound 30 combined with autophagic inhibitor could be another choice for NSCLC treatment in further investigation.

[Time perception in depressed and manic patients].

OBJECTIVE: To investigate the time perception in affective disorders by using neuropsychological tests and to try to elucidate its neurobiochemical mechanism. METHODS: Using a time reproduction task, a comparative study was conducted for 28 depressive patients, 22 manic patients, and 26 age and education level matched healthy persons as healthy controls. RESULTS: Both depressive patients and manic patients are abnormal (P < 0.001), depressive patients over-reproduced the time interval than healthy controls (600 ms/delay 1 s: 1.6 +/- 0.6, P < 0.001; 600 ms/delay 5 s: 1.7 +/- 0.6, P < 0.001; 3 s/delay 1 s: 3.9 +/- 0.9, P < 0.001; 3 s/delay 5 s: 3.9 +/- 0.7, P < 0.001; 5 s/delay 1 s: 5.9 +/- 1.3, P < 0.001; 5 s/delay 5 s: 6.1 +/- 1.3, P < 0.001), yet manic patients under-reproduced the time interval (600 ms/delay 1 s: 0.7 +/- 0.2, P < 0.01; 600 ms/delay 5 s: 0.6 +/- 0.3, P < 0.001; 3 s/delay 1 s: 1.7 +/- 0.5, P < 0.001; 3 s/delay 5 s: 1.8 +/- 0.6, P < 0.001; 5 s/delay 1 s: 2.9 +/- 0.7, P < 0.001; 5 s/delay 5 s: 3.0 +/- 0.8, P < 0.001). The results of time reproduction task in patients were not related to age, education, duration of illness, number of admission (P > 0.05), but had some relation to severity of illness.And the results were positively correlated with the score of HAMD in depressive patients (six times: r = 0.44, 0.46, 0.73, 0.61, 0.55, 0.50, P < 0.05), but negatively with the score of BRMS in manic patients (six times: r = -0.57, -0.54, -0.71, -0.69, -0.80, -0.71, P < 0.05). CONCLUSION: Emotion will affect one's time perception. And the neurotransmitter in brain may participate in the processes of time perception.