基于类salen配体的二苯基锡配合物的合成、抗肿瘤活性及其与DNA相互作用

利用类salen配体二苯乙二酮苯甲酰腙或二苯乙二酮水杨酰腙与二苯基二氯化锡反应,合成了2个二苯基锡配合物[(C_6H_5(O)C=N—N=C(Ph)—(Ph)C=N—N=C(O)—C_6H_5)_2SnPh_2(CH_3OH)]·3CH_3OH (1)和 [(o-OH—C_6H_4(O)C=N—N=C(Ph)—(Ph)C=N—N=C(O)—(o-OH—C_6H_4))_2SnPh_2(CH_3OH)]·CH_3OH (2),通过IR、~1H NMR、~(13)C NMR、~(119)Sn NMR、元素分析、HRMS 以及X射线单晶衍射等表征了配合物结构。测试了配合物1、2的热稳定性及其对癌细胞的体外抑制活性,发现配合物2对癌细胞NCIH460、HepG2、MCF7表现出略优的抑制活性。利用紫外可见吸收光谱、荧光猝灭光谱研究了配合物2与ct-DNA之间的相互作用,结果表明配合物以嵌入模式与DNA结合。     

Clickable Periodic Mesoporous Organosilicas: Synthesis,Click Reactions,and Adsorption of Antibiotics

Pharmaceutical antibiotics are not easily removed from water by conventional water‐treatment technologies and have been recognized as new emerging pollutants. Herein, we report the synthesis of clickable azido periodic mesoporous organosilicas (PMOs) and their use as adsorbents for the adsorption of antibiotics. Ethane‐bridged PMOs, functionalized with azido groups at different densities, were synthesized by the co‐condensation of 1,2‐bis(trimethoxysilyl)ethane (BTME) and 3‐azidopropyltrimethoxysilane (AzPTMS), in the presence of nonionic‐surfactant triblock‐copolymer P123, in an acidic medium. Four different alkynes were conjugated to azide‐terminated PMOs by means of an efficient click reaction. The clicked PMOs showed improved adsorption capacity (241 μg g^?1) for antibiotics (ciprofloxacin hydrochloride) compared with azido‐functionalized PMOs because of the enhanced π–π stacking interactions. These results indicate that click reactions can introduce multifunctional groups onto PMOs, thus demonstrating the great potential of PMOs for environmental applications.     

Combining [Arene–Ru] with Azocarboxamide to Generate a Complex with Cytotoxic Properties

Azocarboxamide (azcH) has been combined for the first time with [Ru–Cym] to generate metal complexes with N,N‐ and N,O‐coordination mode, [(Cym)Ru(azc)Cl] and [(Cym)Ru(azcH)Cl]⁺[PF₆]^?. Geometric and electronic structures of the complexes are reported along with their in vitro activities against different tumour cell lines and preliminary results on solution chemistry. Compound [(Cym)Ru(azc)Cl] exhibited remarkable cytotoxic properties. It was cell‐type specific and had comparable IC₅₀ values towards both cancer cells and their drug‐resistant subline. A tenfold increase in the sensitivity towards [(Cym)Ru(azc)Cl] was noted for the tumour cells with depleted intracellular glutathione (GSH) level, suggesting the essential role of GSH in cell response to this compound.     

Lead Structures for New Antibacterials: Stereocontrolled Synthesis of a Bioactive Muraymycin Analogue

Naturally occurring muraymycin nucleoside antibiotics represent a promising class of novel antibacterial agents. The structural complexity suggests the investigation of simplified analogues as potential lead structures, which can then be further optimized towards highly potent antimicrobials. Herein we report studies on muraymycin‐derived potential lead structures lacking an aminoribose motif found in most naturally occurring muraymycins. We have identified a 5′‐defunctionalized motif to be ideal in terms of stability and chemical accessibility and have synthesized a full‐length muraymycin analogue based on this structure using a novel fully stereocontrolled route. The obtained 5′‐deoxy analogue of the natural product muraymycin C4 showed good inhibitory properties towards the bacterial target protein MraY, sufficient pharmacokinetic stability and no cytotoxicity against human cells, thus making it a promising lead for antibacterial drug development.     

Total Synthesis of the Antibiotic Kendomycin: A Macrocyclization Using the Tsuji–Trost Etherification

A highly stereocontrolled, convergent total synthesis of kendomycin [(?)‐TAN2162], an ansa‐macrocyclic antibiotic, is reported. The key of the strategy is an unprecedented Tsuji–Trost macrocyclic etherification, followed by a transannular Claisen rearrangement to construct the 18‐membered carbocyclic framework. The oxa‐six‐ and five‐membered rings were also stereoselectively constructed respectively by a cascade oxidative cyclization at an unfunctionalized benzylic position and using a one‐pot epoxidation/5‐exo‐tet epoxide opening.     

Immuno‐Chemotherapeutic Platinum(IV) Prodrugs of Cisplatin as Multimodal Anticancer Agents

There is growing consensus that the clinical therapeutic efficacy of some chemotherapeutic agents depends on their off‐target immune‐modulating effects. Pt anticancer drugs have previously been identified to be potent immunomodulators of both the innate and the adaptive immune system. Nevertheless, there has been little development in the rational design of Pt‐based chemotherapeutic agents to exploit their immune‐activating capabilities. The FPR1/2 formyl peptide receptors are highly expressed in immune cells, as well as in many metastatic cancers. Herein, we report a rationally designed multimodal Pt^IV prodrug containing a FPR1/2‐targeting peptide that combines chemotherapy with immunotherapy to achieve therapeutic synergy and demonstrate the feasibility of this approach.     

A Straightforward Approach towards Cyclic Photoactivatable Tubulysin Derivatives

The development of a new photolabile protecting group containing an additional allyl functionality allows the synthesis of cyclic photoactivatable natural products. Cyclization occurs between the allyl moiety in the protecting group and a second double bond in the target molecule by means of ring‐closing metathesis. Cyclization should increase the metabolic stability towards proteases. On the other hand, the conformational change should cause diminished biological activity. As illustrated for tubulysin derivatives, cyclic and photoactivatable drug candidates can easily be obtained in only two steps from simple building blocks through Ugi reaction and ring‐closing metathesis. The photolabile protecting group is introduced by means of the isocyanide component during the Ugi reaction.     

Platinum(II)–Gadolinium(III) Complexes as Potential Single‐Molecular Theranostic Agents for Cancer Treatment

Theranostic agents are emerging multifunctional molecules capable of simultaneous therapy and diagnosis of diseases. We found that platinum(II)–gadolinium(III) complexes with the formula [{Pt(NH₃)₂Cl}₂GdL](NO₃)₂ possess such properties. The Gd center is stable in solution and the cytoplasm, whereas the Pt centers undergo ligand substitution in cancer cells. The Pt units interact with DNA and significantly promote the cellular uptake of Gd complexes. The cytotoxicity of the Pt–Gd complexes is comparable to that of cisplatin at high concentrations (≥0.1 mM ), and their proton relaxivity is higher than that of the commercial magnetic resonance imaging (MRI) contrast agent Gd–DTPA. T₁‐weighted MRI on B6 mice demonstrated that these complexes can reveal the accumulation of platinum drugs in vivo. Their cytotoxicity and imaging capabilities make the Pt–Gd complexes promising theranostic agents for cancer treatment.     

Probing the Anticancer Mechanism of (−)‐Ainsliatrimer A through Diverted Total Synthesis and Bioorthogonal Ligation

Herein, we report an efficient approach for exploring the novel anticancer mechanism of (?)‐ainsliatrimer A, a structurally complex and unique trimeric sesquiterpenoid, through a combined strategy of diverted total synthesis (DTS) and bioorthogonal ligation (TQ ligation), which allowed us to visualize the subcellular localization of this natural product in live cells. Further biochemical studies facilitated by pretarget imaging revealed that PPARγ, a nucleus receptor, was a functional cellular target of ainsliatrimer A. We also confirmed that the anticancer activity of ainsliatrimer A was caused by the activation of PPARγ.     

Synthesis and Biological Activities of Simplified Analogs of the Natural PKC Ligands,Bryostatin‐1 and Aplysiatoxin

Protein kinase C (PKC) isozymes play central roles in signal transduction on the cell surface and could serve as promising therapeutic targets of intractable diseases like cancer, Alzheimer's disease, and acquired immunodeficiency syndrome (AIDS). Although natural PKC ligands like phorbol esters, ingenol esters, and teleocidins have the potential to become therapeutic leads, most of them are potent tumor promoters in mouse skin. By contrast, bryostatin‐1 (bryo‐1) isolated from marine bryozoan is a potent PKC activator with little tumor‐promoting activity. Numerous investigations have suggested bryo‐1 to be a promising therapeutic candidate for the above intractable diseases. However, there is a supply problem of bryo‐1 both from natural sources and by organic synthesis. Recent approaches on the synthesis of bryo‐1 have focused on its simplification, without decreasing the ability to activate PKC isozymes, to develop new medicinal leads. Another approach is to use the skeleton of natural PKC ligands to develop bryo‐1 surrogates. We have recently identified 10‐methyl‐aplog‐1 ( 26 ), a simplified analog of tumor‐promoting aplysiatoxin (ATX), as a possible therapeutic lead for cancer. This review summarizes recent investigations on the simplification of natural PKC ligands, bryo‐1 and ATX, to develop potential medicinal leads.