A series
of novel compounds bearing a cyclopropyl linkage
were
designed, synthesized, and evaluated as programmed cell death-1 (PD-1)/programmed
cell death-ligand 1 (PD-L1) inhibitors. An optimized compound (1S,2S)-A25 showed potent inhibitory
activity against the PD-1/PD-L1 interaction (IC50 = 0.029
μM) with a selected binding affinity with PD-L1 (K
D = 1.554 × 10–1 μM). Additionally,
under the co-culture with H460/Jurkat cells, (1S,2S)-A25 can reduce the survival of H460 cells
in a concentration-dependent way. A liver microsomal assay revealed
that (1S,2S)-A25 had
favorable metabolic stability. Furthermore, (1S,2S)-A25 displayed favorable pharmacokinetic
properties (oral bioavailability of 21.58%) and potent antitumor potency
in a LLC1 lung carcinoma model without observable side effects. Data
from the flow cytometry and enzyme-linked immunosorbent assays demonstrated
that (1S,2S)-A25 suppressed
the tumor growth by activating the immune microenvironment. Our study
suggests that (1S,2S)-A25 is a promising lead compound for the further development of PD-1/PD-L1
inhibitors.
Aiming at development of potent antitubulin agents targeting colchicine-binding site, a series of novel 5-indolyl-7-arylimidazo[1,2-a]pyridine-8-carbonitrilederivatives (5a–5v and 7a–7h) were designed based on bioisosterism and hybridization strategies. All these compounds were concisely synthesized via a three-step process and examined against five human cancer cell lines (HT-29, A549, MKN-45, MDA-MB-231 and SMMC-7721) along with a normal human cell (L02) in vitro. A structure-activity relationships (SARs) study was carried out and optimization towards this series of compounds in cellular assay resulted in the discovery of 5k, which displayed similar or better antitumor potency against the tested cancer cells with IC50 value ranging from 0.02 to 1.22 μM superior to CA-4 and Crolibulin. Significantly, a cell cycle study disclosed the ability of 5k to arrest cell cycle at the G2/M phase, and immunofluorescence assay as well as a colchicine competition assay revealed that tubulin polymerization was disturbed by 5k by binding to the colchicine site. Moreover, the molecular modeling mode showed the posture of 5k and Crolibulin was similar in the colchcine-binding pocket of tubulin as identified with the SARs and pharmacological results. Together, all these results rationalized 5k might serve as a promising lead for a novel class of antitubulin agents for cancer treatments.
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