Hypoxia-Activated Prodrugs with Dual COX-2/CA Inhibitory Effects on Attenuating Cardiac Inflammation under Hypoxia

Cardiac inflammation is generally accompanied by hypoxia, while myocardial injury and an abnormal microenvironment caused by hypoxia tend to suppress the efficacy of common anti-inflammatory drugs. To improve the anti-inflammatory effect under hypoxia, a hypoxia-activated prodrug HAP1 consisting of a cyclooxygenase-2 (COX-2) inhibitor Ind and a carbonic anhydrase (CA) inhibitor Ace was synthesized. HAP1 was found to be activated by nitroreductase (NTR) under hypoxia to release two pharmacophores and achieve the combinatory medication intensively at the hypoxic site, better than Ind or Ace alone. When NTR activity was inhibited by Na2WO4 under hypoxia, no pharmacophores were found to release from HAP1 without exhibiting its activity. However, the efficacy of the Ind and Ace combination group (I&A) was not affected. Furthermore, HAP1 showed advantages over I&A in vivo not only in improving bioavailability but also in reducing side effects. The HAP approach turns out to inhibit cardiac inflammation efficiently and safely under hypoxia

Hypoxia-Activated Prodrugs with Dual COX-2/CA Inhibitory Effects on Attenuating Cardiac Inflammation under Hypoxia

Cardiac inflammation is generally accompanied by hypoxia, while myocardial injury and an abnormal microenvironment caused by hypoxia tend to suppress the efficacy of common anti-inflammatory drugs. To improve the anti-inflammatory effect under hypoxia, a hypoxia-activated prodrug HAP1 consisting of a cyclooxygenase-2 (COX-2) inhibitor Ind and a carbonic anhydrase (CA) inhibitor Ace was synthesized. HAP1 was found to be activated by nitroreductase (NTR) under hypoxia to release two pharmacophores and achieve the combinatory medication intensively at the hypoxic site, better than Ind or Ace alone. When NTR activity was inhibited by Na2WO4 under hypoxia, no pharmacophores were found to release from HAP1 without exhibiting its activity. However, the efficacy of the Ind and Ace combination group (I&A) was not affected. Furthermore, HAP1 showed advantages over I&A in vivo not only in improving bioavailability but also in reducing side effects. The HAP approach turns out to inhibit cardiac inflammation efficiently and safely under hypoxia

Synthesis and biological evaluation of water-soluble <i>trans</i>-[bicyclo[2.2.2]octane-7<i>R</i>,8<i>R</i>-diamine]platinum(II) complexes with linear or branched alkoxyacetates as leaving groups

<p>Four platinum(II) complexes, <i>trans</i>-[bicyclo[2.2.2]octane-7<i>R</i>,8<i>R</i>-diamine]bis(alkoxyacetato-<i>O</i>,<i>O’</i>) platinum(II) (alkoxyacetate = methoxyacetate (<b>2</b>), ethoxyacetate (<b>3</b>), isopropoxyacetate (<b>4</b>), and <i>tert</i>-butoxyacetate (<b>5</b>)) were synthesized and spectrally characterized. The cytotoxicity of these water-soluble complexes was evaluated by CCK-8 assay <i>in vitro</i> against HCT-116, HepG-2, and A549 cancer cell lines. Most of the complexes had cytotoxic activity against the tested cancer cell lines. Among them, <b>3</b> showed more potent antitumor effect than cisplatin or oxaliplatin. Complex <b>3</b> could cause HCT-116 cell line death based on an apoptotic pathway since it has a dicyclic moiety similar to 1<i>R</i>,2<i>R</i>-diaminocyclohexane in oxaliplatin. Agarose gel electrophoresis on the interaction between <b>3</b> and DNA indicated that it has different behavior from that of cisplatin or oxaliplatin, which has a high correlation with the ligand used.</p

Theranostic Pt(IV) Conjugate with Target Selectivity for Androgen Receptor

It is difficult to diagnose and treat castration-resistant prostate cancer (CRPC) which occurs due to the overexpression of androgen receptor (AR). Because there is a high level of AR in CRPC, we designed and prepared three Pt­(IV)-based prodrugs targeting AR. Among them, compound 3, a three-in-one hybrid (an AR binding ligand, a cisplatin unit, and a coumarin moiety), was found to display satisfactory AR binding affinity and antagonist activity against androgen receptor, which could also be effectively internalized and visualized in LNCaP (AR+) cells. Due to its AR affinity, <b>3</b> selectively accumulated in greater quantities in LNCaP (AR+) cells than in PC-3 (AR-) cells. Moreover, compound <b>3</b> exhibited excellent anticancer activity superior to cisplatin.These results highlight the targeting theranostic application of Pt­(IV) prodrugs

Multitargeting HDAC Inhibitors Containing a RAS/RAF Protein Interfering Unit

In this work, a series of multitargeting histone deacetylase (HDAC) inhibitors capable of regulating the signal transduction between RAS protein and downstream effectors were obtained by introducing a zinc-ion-binding group into the framework of rigosertib via different linkers. Among them, two representative compounds, XSJ-7 and XSJ-10, not only showed stronger antiproliferative activity against many types of cancer cells including solid tumor cells but also presented more potent inhibition on different subtypes of HDAC than suberoylanilide hydroxamic acid (SAHA). Significantly, XSJ-10 presented moderate pharmacokinetic behaviors and showed stronger antitumor activity than oxaliplatin, SAHA, and rigosertib in the HT-29 xenograft mouse models without significant systemic toxicity. Research on the anticancer mechanism of XSJ-10 revealed that it can effectively induce the apoptosis of cancer cells and suppress the tumor by strongly inhibiting the RAS-RAF-MEK-ERK signaling pathway and the acetylation level of HDAC3

Multitargeting HDAC Inhibitors Containing a RAS/RAF Protein Interfering Unit

In this work, a series of multitargeting histone deacetylase (HDAC) inhibitors capable of regulating the signal transduction between RAS protein and downstream effectors were obtained by introducing a zinc-ion-binding group into the framework of rigosertib via different linkers. Among them, two representative compounds, XSJ-7 and XSJ-10, not only showed stronger antiproliferative activity against many types of cancer cells including solid tumor cells but also presented more potent inhibition on different subtypes of HDAC than suberoylanilide hydroxamic acid (SAHA). Significantly, XSJ-10 presented moderate pharmacokinetic behaviors and showed stronger antitumor activity than oxaliplatin, SAHA, and rigosertib in the HT-29 xenograft mouse models without significant systemic toxicity. Research on the anticancer mechanism of XSJ-10 revealed that it can effectively induce the apoptosis of cancer cells and suppress the tumor by strongly inhibiting the RAS-RAF-MEK-ERK signaling pathway and the acetylation level of HDAC3

Multitargeting HDAC Inhibitors Containing a RAS/RAF Protein Interfering Unit

In this work, a series of multitargeting histone deacetylase (HDAC) inhibitors capable of regulating the signal transduction between RAS protein and downstream effectors were obtained by introducing a zinc-ion-binding group into the framework of rigosertib via different linkers. Among them, two representative compounds, XSJ-7 and XSJ-10, not only showed stronger antiproliferative activity against many types of cancer cells including solid tumor cells but also presented more potent inhibition on different subtypes of HDAC than suberoylanilide hydroxamic acid (SAHA). Significantly, XSJ-10 presented moderate pharmacokinetic behaviors and showed stronger antitumor activity than oxaliplatin, SAHA, and rigosertib in the HT-29 xenograft mouse models without significant systemic toxicity. Research on the anticancer mechanism of XSJ-10 revealed that it can effectively induce the apoptosis of cancer cells and suppress the tumor by strongly inhibiting the RAS-RAF-MEK-ERK signaling pathway and the acetylation level of HDAC3

Synthesis of 2‑Alkenylquinoline by Reductive Olefination of Quinoline <i>N</i>‑Oxide under Metal-Free Conditions

Synthesis of 2-alkenylquinoline by reductive olefination of quinoline <i>N</i>-oxide under metal-free conditions is disclosed. Practically, the reaction could be performed with quinoline as starting material via a one-pot, two-step process. A possible mechanism is proposed that involves a sequential 1,3-dipolar cycloaddition and acid-assisted ring opening followed by a dehydration process

Anticancer Platinum(IV) Prodrugs Containing Monoamino­phosphonate Ester as a Targeting Group Inhibit Matrix Metalloproteinases and Reverse Multidrug Resistance

A novel class of platinum­(IV) complexes comprising a monoamino­phosphonate ester moiety, which can not only act as a bone-targeting group but also inhibit matrix metalloproteinases (MMPs), were designed and synthesized. Biological assay of these compounds showed that they had potent antitumor activities against the tested cancer cell lines compared with cisplatin and oxaliplatin and indicated low cytotoxicity to human normal liver cells. Particularly, the platinum­(IV) complexes were very sensitive to cisplatin resistant cancer cell lines. The corresponding structure–activity relationships were studied and discussed. Related mechanism study revealed that the typical complex <b>11</b> caused cell cycle arrest at S phase and induced apoptosis in Bel-7404 cells via a mitochondrial-dependent apoptosis pathway. Moreover, complex <b>11</b> had potent ability to inhibit the tumor growth in the NCI-H460 xenograft model comparable to cisplatin

Study on Antitumor Platinum(II) Complexes of Chiral Diamines with Dicyclic Species as Steric Hindrance

A series of platinum­(II) complexes, characteristic of chiral <i>trans</i>-bicyclo­[2.2.2]­octane-7,8-diamine as ligand possessing dicyclic steric hindrance, were designed and synthesized. Biological evaluation showed that almost all complexes had cytotoxic activity against the tested cancer cell lines, among which most of chiral (<i>R</i>,<i>R</i>)-enantiomeres had stronger cytotoxicity than their (<i>S</i>,<i>S</i>)-counterparts, and <b>2a</b>, [<i>trans</i>-bicyclo­[2.2.2]­octane-7<i>R</i>,8<i>R</i>-diamine]­(oxalato-<i>O</i>,<i>O</i>′)­platinum­(II), is the most effective agent. Significantly, its counterpart, <b>2b</b>, was much more sensitive to cisplatin resistant SGC7901/CDDP cancer cell line at a higher degree than <b>2a</b>. Docking study and agarose gel electrophoresis revealed that the interaction of <b>2a</b> with DNA was similar to that of oxaliplatin. Western blot analysis demonstrated that <b>2a</b> could induce a better effect than cisplatin on a mitochondrial-dependent apoptosis pathway. Kinetic study indicated that the dicyclic ligand can accelerate the reaction rate of the complex