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A series of new isatin/triazole conjugates were designed based on the hypothesis that the ester-linked compounds could be enzymatically hydrolyzed by cellular esterases inside the cells. These compounds showed moderate to good growth inhibition toward the tested cancer cells, exerted selective inhibition toward MGC-803 cells and were less toxic to normal cells HL-7702 and GES-1. Of these compounds, compound 5a showed the best inhibitory activity against MGC-803 cells (IC 50  = 9.78 μM), induced apoptosis through multiple mechanisms, as well as inhibited migration of MGC-803 cells., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Cancer cells always have increased ROS levels, thus making them more vulnerable to persistent endogenous oxidative stress. The biochemical difference between cancer and normal cells could be exploited to achieve selective cancer cell killing by exogenous ROS-producing agents. Herein we described a structurally novel steroidal spirooxindole by241 and its anticancer efficacy. By241 exhibited potent inhibition against human cancer cells and less toxic to normal cells. By241 concentration-dependently induced apoptosis of MGC-803 and EC9706 cells, accompanied with the mitochondrial dysfunction and increased ROS levels. NAC can completely restore the decreased cell viability of MGC-803 cells caused by by241, suggesting ROS-mediated mechanisms. The expression levels of proteins involved in the mitochondrion-related pathways were detected, showing increased expression of proapoptotic proteins and decreased expression of anti-apoptotic proteins, and activation of caspases-9/-3, but without activating caspase-8 expression. Pretreatment with Z-VAD-FMK partially rescued by241-induced apoptosis of MGC-803 cells. Additionally, by241 inhibited mTOR, activated p53 and its downstream proteins, cleaved MDM2 and PI3K/AKT as well as NF-κB signaling pathway. In vivo experiments showed that by241 did not have significant acute oral toxicity and exerted good anticancer efficacy against MGC-803 bearing mice models. Therefore, by241 may serve as a lead for further development for cancer therapy.

A series of steroidal hybrids with different terminal bioactive scaffolds were synthesized using the molecular hybridization approach and further evaluated for their antiproliferative activity against several cancer cell lines of different origins using the MTT assay. The preliminary results indicated that compounds 12a-h with the terminal isatin motif were remarkably sensitive to SH-SY5Y cells, thereby exerting potent growth inhibition in vitro. This selectivity is possibly attributed to LSD1 inactivation (IC50 = 3.18 μM). Besides, we also found that the chloro atom at the 7-position on the isatin core was beneficial for the activity through the SARs studies. Among this series, compound 12g showed the best inhibitory activity (IC50 = 4.06 μM) against SH-SY5Y cells, which was comparable to that of 5-FU. Compound 12g arrested cell cycle at G2/M phase, induced apoptosis accompanied with decrease of mitochondrial membrane potential, and inhibited LSD1 potently (IC50 = 3.18 μM). Docking studies showed that compound 12g formed interactions with surrounding amino acid residues and the steroid nucleus occupied the tubular hydrophobic cavity of the active site. Compounds 13-18 represented weak to moderate activity against the tested cancer cell lines. The steroidal dimer 20 and the structurally simplified non-steroidal dimer 21 were found to be devoid of the inhibitory activity., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

The utility of natural products for identifying anticancer agents has been highly pursued in the last decades and over 100 drug molecules in clinic are natural products or natural product-derived compounds. Natural products are believed to be able to cover unexplored chemical space that is normally not occupied by commercially available molecule libraries. However, the low abundance and synthetic intractability of natural products have limited their applications in drug discovery. Recently, the identification of biologically relevant fragments derived from biologically validated natural products has been recognized as a powerful strategy in searching new biological probes and drugs. The spirocyclic oxindoles, as privileged structural scaffolds, have shown their potential in designing new drugs. Several anticancer drug candidates such as SAR405838, RO8994, CFI-400945 and their bioisosteres are undergoing clinical trials or preclinical studies. To highlight the significant progress, we focus on illustrating the discovery of SAR405838, RO8994, CFI-400945 and their bioisosteres for cancer therapy using substructure-based strategies and discussing modes of action, binding models and preclinical data.

A series of novel steroidal spirooxindoles 3a-h were synthesized from pregnenolone in a high regioselective manner using the 1,3-dipolar cycloaddition as the key step. This protocol resulted in the formation of two C-C bonds, one C-N bond and the creation of one pyrrolidine ring and three contiguous stereocenters in a single operation. Biological evaluation showed that these synthesized steroidal spirooxindoles exhibited moderate to good antiproliferative activity against the tested cell lines and some of them were more potent than 5-FU. Among them, compounds 3e and 3f displayed the best antiproliferative activity against MCF-7 cells with the IC50 values of 4.0 and 3.9μM, respectively. Flow cytometry analysis demonstrated that compound 3d caused the cellular apoptosis and cell cycle arrest at G2/M phase in a concentration-dependent manner. Docking results indicated that compound 3d fitted well into the MDM2 active site 1RV1 by interacting with Lys94 and Thr101 residues., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The identification of novel anticancer agents with high efficacy and low toxicity has always been an intriguing topic in medicinal chemistry. The unique structural features of spirooxindoles together with diverse biological activities have made them promising structures in new drug discovery. “Among spirooxindoles, CFI-400945, recently discovered by Sampson et al., is a potent PLK4 inhibitor, which has entered phase I clinical trials for the treatment of solid tumors. However, questions remain as to whether PLK4 is the only relevant therapeutic target for CFI-400945. To highlight this significant progress of CFI-400945 in last two years, this review centers on the identification from a focused kinase library, structural optimizations and strategies involved, structure-activity relationships, modes of action, target validation, chemical synthesis and, more importantly, the kinase selectivity between PLK4 and other targets [corrected]., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

A series of novel steroidal pyran-oxindole hybrids were efficiently synthesized in a single operation through the vinylogous aldol reaction of vinyl malononitrile 3 with substituted isatins involving the construction of C-C and C-O bonds. Some compounds displayed moderate to good cytotoxicity against T24, SMMC-7721, MCF-7 and MGC-803 cells. Compounds 4f and 4i were more potent than 5-Fu against T24 and MGC-803 cells with the IC50 values of 4.43 and 8.45 μM, respectively. Further mechanism studies indicated that compound 4i induced G2/M arrest and early apoptosis in a concentration- and time-dependent manner., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Two series of novel steroidal spiro-pyrrolidinyl oxindoles 3a-t and 6a-c were designed and synthesized from dehydroepiandrosterone using the 1,3-dipolar cycloaddition as the key step and further evaluated for their antiproliferative activities for four human cancer cell lines (MGC-803, EC109, SMMC-7721 and MCF-7). This protocol achieved the formation of two CC bonds, one CN bond and the creation of one new five-membered pyrrolidine ring and three contiguous stereocenters in a single operation. Biological evaluation showed that these synthesized steroidal spiro-pyrrolidinyl oxindoles possessed moderate to good antiproliferative activities against the tested cell lines and some of them were more potent than 5-Fu. Particularly, compound 3g showed good antiproliferative activity against SMMC-7721 (IC50=0.71μM). Steroid dimer 6b showed improved antiproliferative activities against SMMC-7721 and MCF-7 with the IC50 values of 4.30 and 2.06μM, respectively. Flow cytometry analysis demonstrated that compound 3n caused the cellular early apoptosis and cell cycle arrest at G2/M phase in a concentration- and time-dependent manner. [Corrected], (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The stereoselective and metal-free protocol involving a cascade aldol/cyclization process for the synthesis of steroidal (E, E) dienamides from steroidal α, α-dicyanoalkene was reported. This protocol efficiently achieved the construction of C=C bond and selective conversion of cyano group into carboxamide in one-pot procedure under mild condition. Further biological evaluation showed that some of these compounds had moderate to excellent cytotoxic activities against all the tested cancer cell lines and were more potent than well-known drug 5-fluorouracil. Particularly, compound 3c represented excellent inhibitory effect against MCF-7 (IC50=0.76 μM), which was about 10-fold more potent than 5-fluorouracil., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Two series of steroidal dienamides 4a-q and 5a-f were designed, synthesized and evaluated for cytotoxic activities against five human cancer cell lines (MGC-803, EC109, PC-3, SMMC-7721 and MCF-7). The protocol developed efficiently achieved the construction of carbon-carbon double bond and selective conversion of nitrile group into carboxamide in one-pot procedure. Besides, compounds 4a-q and 5a-f showed moderate to excellent cytotoxic activities with the IC₅₀ values ranging from 0.1 to 40 μM and most of them were more potent than 5-fluorouracil. Particularly, four compounds 4d, 4e, 4q and 5a showed excellent selectivity against MGC-803 with the IC₅₀ values less than 1 μM. Flow cytometry analysis demonstrated that compound 4c caused the cellular early apoptosis and cell cycle arrest in G2/M phase in a concentration-independent manner., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

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