5 research outputs found
Anticancer Platinum(IV) Prodrugs Containing MonoaminoÂphosphonate Ester as a Targeting Group Inhibit Matrix Metalloproteinases and Reverse Multidrug Resistance
A novel
class of platinumÂ(IV) complexes comprising a monoaminoÂphosphonate
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 platinumÂ(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
Three-Component, Four-Molecule, Ru-Catalyzed Cascade Reactions of Indoles and Alkyl Bromides with Sodium Nitrite
<div><p></p><p>An operationally simple domino approach for the ruthenium-catalyzed synthesis of (<i>E</i>)-2,3′-bi(3<i>H</i>-indol)-3-one <i>O</i>-alkyl oximes by the region- and stereoselective three-component, four-molecule reactions of indoles with sodium nitrite and alkyl bromides under mild reaction condition in dimethylformamide is described. Remarkably, multiple bonds including C‒C, C=N, and C‒O bonds were conveniently formed in one pot. The reaction is tolerant to air and is atom economical, in accordance with the concept of modern green chemistry.</p></div
Combretastatin A‑4 Analogue: A Dual-Targeting and Tubulin Inhibitor Containing Antitumor Pt(IV) Moiety with a Unique Mode of Action
Three
new PtÂ(IV) complexes comprising a combretastatin A-4 analogue
were designed and synthesized. The resulting antitumor PtÂ(IV) complexes
could significantly improve the antiproliferative activity and overcome
the drug resistance of cisplatin in vitro. Interestingly, these novel
compounds not only can carry the DNA binding PtÂ(II) warhead into the
cancer cells but also have a small molecule fragment that can inhibit
tubulin polymerization. Among them, complex <b>13</b>, which
was attached to an inhibitor of tubulin at one axial position of PtÂ(IV)
octahedral coordination sphere, could effectively enter cancer cells,
arrest the cell cycle in HepG-2 cancer cells at G2/M phases, and induce
activation of caspases triggering apoptotic signaling via the mitochondrial-dependent
apoptosis pathways. Moreover, complex <b>13</b> has the ability
to effectively inhibit the tumor growth in the HepG-2 xenograft model
without causing significant loss of animal body weight in comparison
with cisplatin
Ligustrazine-Derived Chalcones-Modified Platinum(IV) Complexes Intervene in Cisplatin Resistance in Pancreatic Cancer through Ferroptosis and Apoptosis
Developing multitarget platinum(IV) prodrugs is an important
strategy
to attenuate cisplatin (CDDP) resistance in tandem with reduced toxicity.
Herein, six novel ligustrazine-derived chalcones-modified platinum(IV)
complexes were synthesized and evaluated for their anti-proliferative
activities. Among them, 16a displayed higher cytotoxicity
toward the tested cancer cell lines and lower cytotoxicity toward
the human normal cells than CDDP or the combined group. Mechanistic
studies revealed that 16a efficiently induced DNA damage
and initiated a mitochondria-dependent apoptosis pathway. Besides, 16a significantly triggered ferroptosis by down-regulating
expression levels of nuclear factor erythroid 2-related factor 2,
glutathione peroxidase 4, and solute carrier family 7 member 11. Further, 16a obtained superior in vivo anti-tumor efficiency than CDDP
in CDDP-resistant pancreatic cancer xenograft models but showed no
significant side effects. In summary, our study suggested that 16a acts via a different anti-cancer mechanistic pathway than
CDDP and may therefore encompass a novel practical strategy for cancer
treatment
Ligustrazine-Derived Chalcones-Modified Platinum(IV) Complexes Intervene in Cisplatin Resistance in Pancreatic Cancer through Ferroptosis and Apoptosis
Developing multitarget platinum(IV) prodrugs is an important
strategy
to attenuate cisplatin (CDDP) resistance in tandem with reduced toxicity.
Herein, six novel ligustrazine-derived chalcones-modified platinum(IV)
complexes were synthesized and evaluated for their anti-proliferative
activities. Among them, 16a displayed higher cytotoxicity
toward the tested cancer cell lines and lower cytotoxicity toward
the human normal cells than CDDP or the combined group. Mechanistic
studies revealed that 16a efficiently induced DNA damage
and initiated a mitochondria-dependent apoptosis pathway. Besides, 16a significantly triggered ferroptosis by down-regulating
expression levels of nuclear factor erythroid 2-related factor 2,
glutathione peroxidase 4, and solute carrier family 7 member 11. Further, 16a obtained superior in vivo anti-tumor efficiency than CDDP
in CDDP-resistant pancreatic cancer xenograft models but showed no
significant side effects. In summary, our study suggested that 16a acts via a different anti-cancer mechanistic pathway than
CDDP and may therefore encompass a novel practical strategy for cancer
treatment