Thiazole Functionalization of Thiosemicarbazone for Cu(II) Complexation: Moving toward Highly Efficient Anticancer Drugs with Promising Oral Bioavailability.
Song-Yu LuoChun-Mei ZengPing XuYe NingMeng-Lin DongWen-Hua ZhangGuangliang YuPublished in: Molecules (Basel, Switzerland) (2024)
In this work, we report the synthesis of a new thiosemicarbazone-based drug of N'-(di(pyridin-2-yl)methylene)-4-(thiazol-2-yl)piperazine-1-carbothiohydrazide (H L ) featuring a thiazole spectator for efficient coordination with Cu(II) to give [CuCl( L )] 2 ( 1 ) and [Cu(NO 3 )( L )] 2 ( 2 ). Both 1 and 2 exhibit dimeric structures ascribed to the presence of di-2-pyridylketone moieties that demonstrate dual functions of chelation and intermolecular bridging. H L , 1 , and 2 are highly toxic against hepatocellular carcinoma cell lines Hep-G2, PLC/PRF/5, and HuH-7 with half maximal inhibitory concentration (IC 50 ) values as low as 3.26 nmol/mL (H L ), 2.18 nmol/mL ( 1 ), and 2.54 × 10 -5 nmol/mL ( 2 ) for PLC/PRF/5. While the free ligand H L may elicit its anticancer effect via the sequestration of bio-relevant metal ions (i.e., Fe 3+ and Cu 2+ ), 1 and 2 are also capable of generating cytotoxic reactive oxygen species (ROS) to inhibit cancer cell proliferation. Our preliminary pharmacokinetic studies revealed that oral administration (per os, PO) of H L has a significantly longer half-life t 1/2 of 21.61 ± 9.4 h, nearly doubled as compared with that of the intravenous (i.v.) administration of 11.88 ± 1.66 h, certifying H L as an effective chemotherapeutic drug via PO administration.
Keyphrases
- aqueous solution
- highly efficient
- reactive oxygen species
- metal organic framework
- cell proliferation
- papillary thyroid
- cell death
- dna damage
- biofilm formation
- cell cycle
- emergency department
- heart rate
- high resolution
- adverse drug
- squamous cell carcinoma
- resistance training
- blood pressure
- single cell
- low dose
- signaling pathway
- visible light
- mass spectrometry
- cystic fibrosis
- young adults
- case control
- electronic health record