What blocks more anticancer platinum complexes from experiment to clinic: Major problems and potential strategies from drug design perspectives

2021 ◽  
Vol 449 ◽  
pp. 214210
Kun Peng ◽  
Bing-Bing Liang ◽  
Wenting Liu ◽  
Zong-Wan Mao
Rajiv Sharma ◽  
Vikram Jeet Singh ◽  
Pooja A Chawla

Background: The platinum (II) complexes as anticancer agents have been well explored for the development of novel analogs. Yet, none of them achieved clinical importance in oncology. At present, anticancer compounds containing platinum (II) complexes have been employed in the treatment of colorectal, lung, and genitourinary tumors. Among the platinum-based anticancer drugs, Cisplatin (cis-diamine dichloroplatinum (II), cis-[Pt(NH3)2Cl2]) is one of the most potent components of cancer chemotherapy. The nephrotoxicity, neurotoxicity and ototoxicity, and platinum compounds associated resistant cancer are some major disadvantages. Objective: With the rapidly growing interest in platinum (II) complexes in tumor chemotherapy, researchers have synthesized many new platinum analogs as anticancer agents that show better cytotoxicity, and less off-target effects with less cellular resistance. This follows the introduction of oxaliplatin, water-soluble carboplatin, multinuclear platinum and newly synthesized complexes, etc. Method: This review emphasizes recent advancements in drug design and development, the mechanism of platinum (II) complexes, their stereochemistry, current updates, and biomedical applications of platinum-based anticancer agents. Conclusion: In the last few decades, the popularity of platinum complexes as potent anti-cancer agents has risen as scientists have synthesized many new platinum complexes that exhibit better cytotoxicity coupled with less off-target effects.

Planta Medica ◽  
2009 ◽  
Vol 75 (05) ◽  
pp. 501-507 ◽  
Antonio Evidente ◽  
Artem Kireev ◽  
Aaron Jenkins ◽  
Anntherese Romero ◽  
Wim Steelant ◽  

2011 ◽  
Vol 18 (4) ◽  
pp. 202-207
Catherine Heurteaux ◽  
Jean Mazella ◽  
Marc Borsotto

2013 ◽  
Vol 288 (29) ◽  
pp. 20896-20907 ◽  
Isabel Cruz-Gallardo ◽  
Irene Díaz-Moreno ◽  
Antonio Díaz-Quintana ◽  
Antonio Donaire ◽  
Adrián Velázquez-Campoy ◽  

The discovery of effective new antimalarial agents is urgently needed. One of the most frequently studied molecules anchored to the parasite surface is the merozoite surface protein-1 (MSP1). At red blood cell invasion MSP1 is proteolytically processed, and the 19-kDa C-terminal fragment (MSP119) remains on the surface and is taken into the red blood cell, where it is transferred to the food vacuole and persists until the end of the intracellular cycle. Because a number of specific antibodies inhibit erythrocyte invasion and parasite growth, MSP119 is therefore a promising target against malaria. Given the structural homology of cupredoxins with the Fab domain of monoclonal antibodies, an approach combining NMR and isothermal titration calorimetry (ITC) measurements with docking calculations based on BiGGER is employed on MSP119-cupredoxin complexes. Among the cupredoxins tested, rusticyanin forms a well defined complex with MSP119 at a site that overlaps with the surface recognized by the inhibitory antibodies. The addition of holo-rusticyanin to infected cells results in parasitemia inhibition, but negligible effects on parasite growth can be observed for apo-rusticyanin and other proteins of the cupredoxin family. These findings point to rusticyanin as an excellent therapeutic tool for malaria treatment and provide valuable information for drug design.

2020 ◽  
Vol 295 (37) ◽  
pp. 13047-13064 ◽  
Elfriede Dall ◽  
Florian B. Zauner ◽  
Wai Tuck Soh ◽  
Fatih Demir ◽  
Sven O. Dahms ◽  

The vacuolar cysteine protease legumain plays important functions in seed maturation and plant programmed cell death. Because of their dual protease and ligase activity, plant legumains have become of particular biotechnological interest, e.g. for the synthesis of cyclic peptides for drug design or for protein engineering. However, the molecular mechanisms behind their dual protease and ligase activities are still poorly understood, limiting their applications. Here, we present the crystal structure of Arabidopsis thaliana legumain isoform β (AtLEGβ) in its zymogen state. Combining structural and biochemical experiments, we show for the first time that plant legumains encode distinct, isoform-specific activation mechanisms. Whereas the autocatalytic activation of isoform γ (AtLEGγ) is controlled by the latency-conferring dimer state, the activation of the monomeric AtLEGβ is concentration independent. Additionally, in AtLEGβ the plant-characteristic two-chain intermediate state is stabilized by hydrophobic rather than ionic interactions, as in AtLEGγ, resulting in significantly different pH stability profiles. The crystal structure of AtLEGβ revealed unrestricted nonprime substrate binding pockets, consistent with the broad substrate specificity, as determined by degradomic assays. Further to its protease activity, we show that AtLEGβ exhibits a true peptide ligase activity. Whereas cleavage-dependent transpeptidase activity has been reported for other plant legumains, AtLEGβ is the first example of a plant legumain capable of linking free termini. The discovery of these isoform-specific differences will allow us to identify and rationally design efficient ligases with application in biotechnology and drug development.

2009 ◽  
Vol 284 (38) ◽  
pp. 25697-25703 ◽  
Iain D. Kerr ◽  
Ji H. Lee ◽  
Christopher J. Farady ◽  
Rachael Marion ◽  
Mathias Rickert ◽  

RSC Advances ◽  
2018 ◽  
Vol 8 (5) ◽  
pp. 2315-2322 ◽  
Dong Xu ◽  
Nikolai Smolin ◽  
Rance K. Shaw ◽  
Samuel R. Battey ◽  
Aoxiang Tao ◽  

We discovered molecular evidence that links PEGylation to improved clinical performance, yet at the expense of decreased bioactivity. Our computational approach will facilitate PEGylated protein drug design and optimize its overall therapeutic efficacy.

2019 ◽  
Vol 48 (1) ◽  
pp. 202-208 ◽  
Mattia Fontani ◽  
Eleonora Garoni ◽  
Alessia Colombo ◽  
Claudia Dragonetti ◽  
Simona Fantacci ◽  

For platinum complexes bearing a cyclometallated 5-thiophene-1,3-di(2-pyridyl)benzene, βEFISH increases following the order of the LUMO stabilization.

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