Synthesis of CDDO–Amino Acid–Nitric Oxide Donor Trihybrids as Potential Antitumor Agents against Both Drug-Sensitive and Drug-Resistant Colon Cancer

Abstract

Seventeen CDDO-amino acid-NO donor trihybrids (4a-q) were designed and synthesized. Biological evaluation indicated that the most active compound 4c produced high levels of NO and inhibited the proliferation of drug-sensitive (HCT-8, IC50 = 0.294 μM) and drug-resistant (HCT-8/5-FU, IC50 = 0.232 μM) colon cancer cells, which were attenuated by an NO scavenger or typical substrate of PepT1. Furthermore, 4c triggered HCT-8 and HCT-8/5-FU cell apoptosis more strongly than CDDO-Me, inhibited the HIF-1α, Stat3, AKT, and ERK signaling, and induced the nitration of P-gp, MRP1, and BCRP proteins in HCT-8/5-FU cells. Finally, 4c had 4.36-5.53-fold less inhibitory activity against nontumor colon epithelial-like cells (CCD841, IC50 = 1.282 μM) in vitro and inhibited the growth of implanted human drug-resistant colon cancers in mice more potently than CDDO-Me. Together, 4c is a novel trihybrid with potent antitumor activity and may be a promising candidate for the treatment of drug-resistant colon cancer.

Discovery of novel antitumor nitric oxide-donating β -elemene hybrids through inhibiting the PI3K/Akt pathway

“…The bound antibodies were detected by horseradish peroxidase (HRP) conjugated second antibodies and visualized using an enhanced chemiluminescent reagent. The relative levels of each signaling event to control GAPDH were determined by densimetric scanning [20,29,40].…”

“…In recent decade, numerous efforts were directed towards the construction of hybrids incorporating furoxan subunits to advance the pharmacological profile of the parent drug. Many studies have shown that (phenylsulfonyl)furoxanbased NO-releasing natural products possessed greater antitumor activity than corresponding parent compounds, furoxan precursors and/or their combinations in vitro and in vivo [19][20][21][22].…”

NO-Releasing Enmein-Type Diterpenoid Derivatives with Selective Antiproliferative Activity and Effects on Apoptosis-Related Proteins

“…Nitric oxide (NO), one of the simplest, odorless, colorless, highly reactive, and biological molecules in nature, is a free radical and a key mediator involved in diverse physiological and pathological processes [16][17][18][19][20]. NO-donating compounds have recently come into focus for the treatment of tumors because NO plays a central role in cell regulatory pathways and is a key signaling molecule involved in the death and apoptosis of tumor cells [21][22][23][24][25][26][27][28][29][30][31][32]. Generally, high levels of NO (above 400 nM [33]) produced from NO donors can induce apoptosis, inhibit metastasis of tumor cells, and sensitize tumor cells to radiation, immunotherapy, and chemotherapy.…”

“…Generally, high levels of NO (above 400 nM [33]) produced from NO donors can induce apoptosis, inhibit metastasis of tumor cells, and sensitize tumor cells to radiation, immunotherapy, and chemotherapy. Some synthesized NO-releasing compounds have already shown antitumor activity against human carcinoma cells in vitro and in vivo [21][22][23][24][25][26][27][28][29][30][31][32]. Due to the highly reactive nature of NO, it is difficult to predict its biological effects on a given system from single doses even if provided by the longer action of inducible nitric oxide synthase (iNOS).…”

“…At the same time, the selectivity between tumor and normal cells was observed, since low antiproliferative activity was obtained against the L-02 cell line. Besides, the anticancer potency of triterpenoid/furoxan-based NO-donating analogues against multidrug-resistant cancer cells was also developed by Zhang's group [32,43]. Some furoxan-based NO donor/coumarin [40] and diterpenoid [44] hybrids were also developed as antitumor agents.…”