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Catalytic asymmetric hydroboration of fluoroalkyl‐substituted alkenes is a straightforward approach to access chiral small molecules possessing both fluorine and boron atoms. However, enantioselective hydroboration of fluoroalkyl‐substituted alkenes without fluorine elimination has been a long‐standing challenge in this field. Herein, a copper‐catalyzed hydroboration of difluoroalkyl‐substituted internal alkenes with high levels of regio‐ and enantioselectivities is reported. The native carbonyl directing group, copper hydride system, and bisphosphine ligand play crucial roles in suppressing the undesired fluoride elimination. This atom‐economic protocol provides a practical synthetic platform to obtain a wide scope of enantioenriched secondary boronates bearing the difluoromethylene moieties under mild conditions. Synthetic applications including functionalization of biorelevant molecules, versatile functional group interconversions, and preparation of difluoroalkylated Terfenadine derivative are also demonstrated. [ABSTRACT FROM AUTHOR]

Abstract To explore anti-gastric cancer agents with high efficacy and selectivity, we report the design, synthesis and optimization of a novel series of 3-(2,6,9-trisubstituted-9H-purine)-8-chalcone derivatives starting from the compound PCA-15 reported by us previously. Most of the target compounds demonstrated significant antiproliferative effects on MGC803 cancer cell line, and more potent than the positive control (PCA-15 and 5-Fu). Among them, compound 6o was identified to be the most active compound against MGC803 cell line with an IC 50 value of 0.84 μM. Additionally, high selectivity was also observed between cancer and normal cells (23.35 μM against GES-1). Further mechanism studies confirmed that compound 6o could inhibit colony formation and migration, induce the apoptosis of MGC803 cells through both the mitochondrial-mediated intrinsic pathway and death receptor-mediated extrinsic pathway, which were evidenced by the up-regulation of Bax, cleaved-caspase 9/3/8, cleaved PARP and down-regulation of Bcl-2. Our systematic studies implied a new scaffold targeting gastric cancer cells for further development of small-molecule compounds with improved potency and selectivity. Graphical abstract Image 1 Highlights • A novel purine-chalcone scaffold was established by structural optimization, which led to a gradually improved activity. • Compound 6o exerted the potent anti-gastric cancer activity and good selectivity between cancer and normal cells. • Compound 6o could inhibit migration and induce the apoptosis of MGC803 cells. [ABSTRACT FROM AUTHOR]

A new series of 6-chloro-2-(propylthio)-8,9-dihydro-7H-purine-8-caboxamide derivatives were designed, synthesized, and further evaluated for their antiproliferative activities on four human cancer cell lines (A549, MGC803, PC-3 and TE-1). The structure-activity relationships (SARs) studies were conducted through the variation in the two regions, which including position 8 and 9, of purine core. One of the compounds, 8 , containing a terminal piperazine appendage with a carboxamide moiety at position 8 and phenyl group at position 9 of 6-chloro-8,9-dihydro-7H-purine core, showed the most potent antiproliferative activity and good selectivity between cancer and normal cells (IC 50 values of 2.80 μM against A549 and 303.03 μM against GES-1, respectively). In addition, compound 8 could inhibit the colony formation and migration of A549 cells in a concentration-dependent manner, as well as induce the apoptosis possibly through the intrinsic pathway. [ABSTRACT FROM AUTHOR]

Pteridines are an important class of heterocyclic compounds with diverse biological activities. Here, we report a series of pteridin-7(8 H )-one derivatives and their antiproliferative activities toward MKN-45, MGC-803, EC-109, and H1650. Structure-activity relationship studies showed that compound 12 exerted the most potent antiproliferative activity against MKN-45 and MGC-803 with the IC 50 values of 4.32 and 7.01 μM, respectively. Besides, compound 12 induced morphological changes and apoptosis of MKN-45 cells, increased expression of Bax, down-regulated expression of Bcl-2 and caused cleavage of caspase-3/9. Additionally, we first reported the construction of the novel bicyclic 8,9-dihydro-7 H -purine-8-carboxylate scaffold through the competitive 5-endo cyclization reaction with two C-N bonds and a chiral carbon center established. [ABSTRACT FROM AUTHOR]

The multidrug resistance (MDR) phenomenon in cancer cells is the major obstacle leading to failure of chemotherapy accompanied by the feature of intractable and recurrence of cancers. As significant contributors that cause MDR, ABC superfamily proteins can transport the chemotherapeutic drugs out of the tumor cells by the energy of adenosine triphosphate (ATP) hydrolysis, thereby reducing their intracellular accumulation. The ABC transports like ABCB1, ABCC1 and ABCG2 have been extensively studied to develop modulators for overcoming MDR. To date, no reversal agents have been successfully marketed for clinical application, and little information about the ABC proteins bound to specific inhibitors is known, which make the design of MDR inhibitors with potency, selectivity and low toxicity a major challenge. In recent years, it has been increasingly recognized that pyrimidine-based derivatives have the potential for reversing ABC-mediated MDR. In this review, we summarized the pyrimidine-based inhibitors of ABC transporters, and mainly focused on their structure optimizations, development strategies and structure-activity relationship studies in hope of providing a reference for medicinal chemists to develop new modulators of MDR with highly potency and fewer side effects. Image 1 • ABC transports have been studied to develop modulators for overcoming MDR. • Pyrimidine is an attractive scaffold to develop inhibitors of ABC-mediated MDR. • The advances of pyrimidine-based ABC inhibitors were reviewed. • The SAR and development strategies of pyrimidine-based inhibitors were discussed. [ABSTRACT FROM AUTHOR]

A series of hybrid molecules containing [1,2,3]triazolo[4,5-d]pyrimidine and thiosemicarbazide moieties were designed, synthesized and evaluated for their antiproliferative activities against MGC-803, NCI-H1650 and PC-3 human cancer cells. Some of the synthesized compounds showed moderate to good activity against three selected cancer cell lines. Among these compounds, compound 29 displayed the most potent antiproliferative activity as well as good selectivity between cancer cells and normal cells. Further mechanism studies revealed that compound 29 could obviously inhibit the colony formation and migration of MGC-803 as well as induced apoptosis. [ABSTRACT FROM AUTHOR]

A series of new [1,2,3]triazolo[4,5- d ]pyrimidine/thiourea hybrids were designed and synthesized through the scaffold replacement/ring cleavage strategy. SARs studies revealed that the N -heteroarene moiety attached to the thiourea is preferred over the phenyl ring for the R 2 substituents, while the hydrophobic aromatic group is beneficial for improving the activity. Among these compounds, compound 5r significantly inhibited cell growth of lung cancer cell lines H1650 and A549 (IC 50 = 1.91, 3.28 μM, respectively), but was less toxic against the normal cell line GES-1 (IC 50 = 27.43 μM). Mechanistic studies showed that compound 5r could remarkably inhibit the colony formation of H1650 cells, induced apoptosis possibly through the intrinsic apoptotic pathways, and arrested the cell cycle at G2/M phase. Our studies suggest that the [1,2,3]triazolo[4,5- d ]pyrimidine/thiourea hybrids are a new class of chemotypes possessing interesting antiproliferative activity against lung cancer cells and could be potentially utilized for designing new antitumor agents. [ABSTRACT FROM AUTHOR]

A series of structurally new diheteroaryl thioether analogs was designed, prepared and screened toward MGC-803, MKN-45, EC-109 and H1650. Most of the target compounds displayed moderate to potent antiproliferative activities. Among them, compound 5 showed the best antiproliferative activity against the tested cell lines with the half maximal inhibitory concentration (IC 50 ) values below 10 μM. In addition, flow cytometry analysis showed that compound 5 increased Bax expression, down-regulated expression of Bcl-2, cleaved caspases-3/9, finally inducing apoptosis of MKN-45 cells as well as arrested the cell cycle at G2/M phase. This study suggests that the diheteroaryl thioethers are a class of emerging chemotypes for developing antitumor agents or biological probes, and compound 5 could serve as a good starting point to design new apoptosis inducers. [ABSTRACT FROM AUTHOR]

Pteridines are an important class of fused heterocycles found in natural products and drug molecules, and have shown diverse biological activities. A focused library of 5,8-dihydropteridine-6,7-dione derivatives were designed and evaluated for their antiproliferative activity against MGC-803, SGC-7901, A549 and PC-3 cancer cell lines. The SARs studies highlighted the importance of the piperazine substituted 5,8-dihydropteridine-6,7-dione frameworks for the activity and revealed essential structural elements. Among these compounds, compound 5n displayed the most potent and broad-spectrum antiproliferative inhibition against the tested cell lines and was sensitive to MGC-803 cell line, slightly more potent than 5-FU. Preliminary mechanistic studies showed that compound 5n could inhibit the colony formation and migration of MGC-803 cells. Besides, flow cytometry analysis showed that compound 5n concentration-dependently induced apoptosis of MGC-803 cells. Our studies suggest that the piperazine substituted 5,8-dihydropteridine-6,7-dione frameworks may be regarded as new chemotypes for designing effective antitumor agents targeting gastric cancer cells. [ABSTRACT FROM AUTHOR]

A series of thiazolo[5,4- d ]pyrimidine derivatives were designed through the atom replacement strategy based on biologically validated scaffolds and then evaluated for their antiproliferative activities on cancer cell lines. The structure-activity relationship studies were conducted, leading to the identification of compound 22 , which exhibited good antiproliferative activity against HGC-27 with an IC 50 value of 1.22 μM and low toxicity against GES-1 cells. Mechanistic studies showed that compound 22 inhibited the colony formation and migration of HGC-27 as well as induced apoptosis. The western blot experiments proved that compound 22 up-regulated expression of Bax, down-regulated expression levels of Bcl-2 and cleaved caspased-3/9. These findings indicate that compound 22 may serve as a template for designing new agents for the treatment of human gastric cancers. The atom replacement strategy could be viable strategy for designing new anticancer drugs and may find its applications in drug design. [ABSTRACT FROM AUTHOR]

A series of thiazolo[5,4-d]pyrimidine derivatives were synthesized and evaluated for their antiproliferative activities on three cancer cell lines. The structure-activity relationship studies were conducted through the variation in the three regions of the thiazolo-pyrimidine core. Substitution with morpholine led to compound 24 , which exerted the most potent antiproliferative activity as well as good selectivity between cancer and normal cells (IC 50 values of 1.03 μM against MGC803 and 38.95 μM against GES-1). In addition, compound 24 inhibited the colony formation and migration of MGC803 as well as induced apoptosis. Western blot experiments indicated the expression changes of apoptosis-related proteins, including up-regulation of Bax and caspase-3/9, as well as down-regulation of Bcl-2. [ABSTRACT FROM AUTHOR]

Lysine specific demethylase 1 (LSD1) plays an essential role in maintaining a balanced methylation status at histone tails. Overexpression of LSD1 has been involved in the development of a variety of human diseases, including cancers. Herein, on the basis of our previously developed LSD1 inhibitors, two series of new [1,2,3]triazolo[4,5- d ]pyrimidine derivatives incorporating (thio)urea moiety were designed and evaluated for their LSD1 inhibitory abilities, leading to a novel chemical class of LSD1 inhibitors. Among them, compound 31 was found to moderately inhibit LSD1 activity, as well as increase the expression of H3K4me2 at the cellular level. This compound also showed good selectivity against MAO-A/-B, and a panel of kinases such as CDK and BTK. Besides, the MTT assay suggested that the selected compounds could inhibit the proliferation of LSD1-overexpressed cancer cells. Although this class of compounds only showed moderate anti-LSD1 activity in the micromolar range, this work presents a novel chemotype of LSD1 inhibitors with good enzyme selectivity as well as cellular LSD1 inhibitory activity, and could provide a useful template for the development of more potent LSD1 inhibitors for cancer treatment. Image 1 • The [1,2,3]triazolo[4,5- d ]pyrimidin-7-one/(thio)urea hybrids represent a new chemical class of LSD1 inhibitors. • Compound 31 had moderate inhibitory activity against LSD1. • Compound 31 had good enzyme selectivity. • The selected LSD1 inhibitors had antiproliferative activity against LSD1-overexpressed tumor cells. [ABSTRACT FROM AUTHOR]