Ferrocene-appended pharmacophores: an exciting approach for modulating the biological potential of organic scaffolds

Singh, Amandeep; Lumb, Isha; Mehra, Vishu; Kumar, Vipan

doi:10.1039/c8dt03440k

Cited by 117 publications

(82 citation statements)

References 53 publications

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“…Here, the peptide reported, RP1, is derived from the human chemokine CLX4 [36] and modulates immune responses by protecting the host through a series of mechanisms: chemotactic activity, attracting leukocytes; modulation of host cell responsiveness to TLR ligands; stimulation of angiogenesis; increase in activation and differentiation of leukocyte/monocyte; modulation of expression of cytokines/chemokines; and proinflammatory [72][73][74]. In antiparasitic studies, the peptide can modulate the concentration of IL-12, inducing immune responses, besides stimulating the production of nitric oxide of the host and of IFN λ, making the infected cell to fight the parasite [68,72,[75][76][77][78][79].…”

Section: Plos Onementioning

confidence: 99%

“…In biological medium, this molecule is oxidized to the cation-radical ferrocene by hydrogen peroxide in the presence of the enzyme peroxidase, inducing cellular stress [37]. The physico-chemical properties, redox process, and the high reactivity on the biological activity of the Fc molecule [74], may explain the increase in the cytotoxic effect of the conjugated [64,70,75]. The toxicity of the conjugate can be justified by the lipophilicity property of Fc, that could increase the interaction with the membrane of the macrophage.…”

Section: Plos Onementioning

confidence: 99%

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Antimicrobial activity of RP-1 peptide conjugate with ferrocene group

et al. 2020

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Parasitic diseases are a neglected and serious problem, especially in underdeveloped countries. Among the major parasitic diseases, Leishmaniasis figures as an urgent challenge due to its high incidence and severity. At the same time, the indiscriminate use of antibiotics by the population is increasing together with resistance to medicines. To address this problem, new antibiotic-like molecules that directly kill or inhibit the growth of microorganisms are necessary, where antimicrobial peptides (AMPs) can be of great help. In this work, the ferrocene molecule, one active compound with low levels of in vivo toxicity, was coupled to the N-terminus of the RP1 peptide (derived from the human chemokine CXCL4), aiming to evaluate how this change modifies the structure, biological activity, and toxicity of the peptide. The peptide and the conjugate were synthesized using the solid phase peptide synthesis (SPPS). Circular dichroism assays in PBS showed that the RP1 peptide and its conjugate had a typical spectrum for disordered structures. The Fc-RP1 presented antiamastigote activity against Leishmania amazonensis (IC 50 = 0.25 μmol L -1 ). In comparison with amphotericin B, a second-line drug approved for leishmaniasis treatment, (IC 50 = 0.63 μmol L -1 ), Fc-RP1 was more active and showed a 2.5-fold higher selectivity index. The RP1 peptide presented a MIC of 4.3 μmol L -1 against S. agalactiae, whilst Fc-RP1 was four times more active (MIC = 0.96 μmol L -1 ), indicating that ferrocene improved the antimicrobial activity against Gram-positive bacteria. The Fc-RP1 peptide also decreased the minimum inhibitory concentration (MIC) in the assays against E. faecalis (MIC = 7.9 μmol L -1 ), E. coli (MIC = 3.9 μmol L -1 ) and S. aureus (MIC = 3.9 μmol L -1 ). The cytotoxicity of the compounds was tested against HaCaT cells, and no significant activity at the highest concentration tested (500 μg. mL -1 ) was observed, showing the high potential of this new compound as a possible new drug. The coupling of ferrocene also increased the vesicle permeabilization of the peptide, showing a direct relation between high peptide concentration and high carboxyfluorescein release, which indicates the action mechanism by pore formation on the vesicles. Several studies have shown that ferrocene destabilizes cell membranes through lipid peroxidation, leading to cell lysis. It is noteworthy that the Fc-RP1 peptide synthesized here PLOS ONE

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Section: Plos Onementioning

confidence: 99%

Section: Plos Onementioning

confidence: 99%

Antimicrobial activity of RP-1 peptide conjugate with ferrocene group

et al. 2020

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“…Class A contains ferrocene derivatives, which are one of the most common metalcontaining scaffolds explored in medicinal bioinorganic chemistry due to their ease of functionalization, stability, and low cost. 19,39 Ferrocene was rst introduced as a bioisostere for aryl/heteroaryl rings, and ferrocene has been utilized to improve anticancer, antimalarial, and antibacterial properties of organic therapies. 19,29,39 Classes B and C are comprised of cobaltocenes and bis(arene)rhenium scaffolds, which are structurally similar to Class A but possess a positive charge.…”

Section: Metallofragment Library Designmentioning

confidence: 99%

Expanding medicinal chemistry into 3D space: metallofragments as 3D scaffolds for fragment-based drug discovery

et al. 2020

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“…In that frame, the use of biologically essential metals, such as iron, seems to be a valuable strategy [2]. The better-known example is the ferrocifen family of compounds, ferrocenyl analogues of tamoxifen, developed by Jaouen and coworkers [2][3][4][5][6][7][8]. Tamoxifen is the first line chemotherapeutic for patients with hormone-dependent breast cancer (oestrogen receptor α-positive, ERα+).…”

Section: Introductionmentioning

confidence: 99%

A New Family of Iron(II)-Cyclopentadienyl Compounds Shows Strong Activity against Colorectal and Triple Negative Breast Cancer Cells

et al. 2020

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A family of compounds with the general formula [Fe(η5-C5H5)(CO)(PPh3)(NCR)]+ has been synthesized (NCR = benzonitrile (1); 4-hydroxybenzonitrile (2); 4-hydroxymethylbenzonitrile (3); 4-aminobenzonitrile (4); 4-bromobenzonitrile (5); and, 4-chlorocinnamonitrile (6)). All of the compounds were obtained in good yields and were completely characterized by standard spectroscopic and analytical techniques. Compounds 1, 4, and 5 crystallize in the monoclinc P21/c space group and packing is determined by short contacts between the phosphane phenyl rings and cyclopentadienyl (compounds 1 and 4) or π-π lateral interactions between the benzonitrile molecules (complex 5). DFT and TD-DFT calculations were performed to help in the interpretation of the experimental UV-Vis. data and assign the electronic transitions. Cytotoxicity studies in MDA-MB-231 breast and SW480 colorectal cancer-derived cell lines showed IC50 values at a low micromolar range for all of the compounds in both cell lines. The determination of the selectivity index for colorectal cells (SW480 vs. NCM460, a normal colon-derived cell line) indicates that the compounds have some inherent selectivity. Further studies on the SW480 cell line demonstrated that the compounds induce cell death by apoptosis, inhibit proliferation by inhibiting the formation of colonies, and affect the actin-cytoskeleton of the cells. These results are not observed for the hydroxylated compounds 2 and 3, where an alternative mode of action might be present. Overall, the results indicate that the substituent at the nitrile-based ligand is associated to the biological activity of the compounds.

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Ferrocene-appended pharmacophores: an exciting approach for modulating the biological potential of organic scaffolds

Abstract: The present review article describes the recent developments (2014–18) on the synthesis of ferrocene-based pharmacophores with the specific benefits of introducing/replacing organic pharmacophores with the ferrocene core for desired bioactivities.

Cited by 117 publications

References 53 publications

Antimicrobial activity of RP-1 peptide conjugate with ferrocene group

Antimicrobial activity of RP-1 peptide conjugate with ferrocene group

Expanding medicinal chemistry into 3D space: metallofragments as 3D scaffolds for fragment-based drug discovery

A New Family of Iron(II)-Cyclopentadienyl Compounds Shows Strong Activity against Colorectal and Triple Negative Breast Cancer Cells

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