In the face of the recent pandemic and emergence of infectious diseases of viral origin, research on parasitic diseases such as malaria continues to remain critical and innovative methods are ...required to target the rising widespread resistance that renders conventional therapies unusable. The prolific use of auxiliary metallo-fragments has augmented the search for novel drug regimens in an attempt to combat rising resistance. The development of organometallic compounds (those containing metal-carbon bonds) as antimalarial drugs has been exemplified by the clinical development of ferroquine in the nascent field of Bioorganometallic Chemistry. With their inherent physicochemical properties, organometallic complexes can modulate the discipline of chemical biology by proffering different modes of action and targeting various enzymes. With the beneficiation of platinum group metals (PGMs) in mind, this review aims to describe recent studies on the antimalarial activity of PGM-based organometallic complexes. This review does not provide an exhaustive coverage of the literature but focusses on recent advances of bioorganometallic antimalarial drug leads, including a brief mention of recent trends comprising interactions with biomolecules such as heme and intracellular catalysis. This resource can be used in parallel with complementary reviews on metal-based complexes tested against malaria.
A small library of aminoquinoline and imidazolopiperidine (IMP)-based ligands, containing the 1,2,3-triazole moiety, and their corresponding tricarbonyl rhenium complexes were synthesised and their ...inhibitory activities evaluated against the chloroquine-sensitive (CQS) and multidrug-resistant (MDR) strains (NF54 and K1, respectively) of P. falciparum. The quinoline-based compounds (L1, L2, ReL1, and ReL2) were at least six-fold more potent than their IMP-based counterparts (L3, L4, ReL3, and ReL4) against both strains of P. falciparum, with the most promising compound (L1) displaying activity comparable to chloroquine diphosphate (CQDP) in the MDR strain. Additionally, all of the synthesised compounds have resistance indices less than CQDP. To gain insight into a possible mechanism of action, in silico hemozoin docking simulations were performed. These studies proposed that the tested compounds may act via hemozoin inhibition, as the new aminoquinoline-derivatives, with the exception of complex ReL2 (binding affinity: -12.62 kcal/mol), showed higher binding affinities than the reference drug chloroquine (CQ, -13.56 kcal/mol). Furthermore, the ligands exhibited superior binding affinity relative to their corresponding Re(I) complexes, which is reflected in their antiplasmodial activity.
The increased success of small metal‐containing molecules as pharmaceutical agents has prompted investigations into the pharmacological activity of a different class of metal‐based compounds; ...supramolecular coordination complexes (SCCs). Such complexes have been extensively investigated for their anticancer activity, with many displaying activities comparable or superior to available clinical chemotherapeutic drugs. Here, we evaluated a series of quinoline‐containing binuclear complexes and metallarectangles for their in vitro anticancer activity in the hormone receptor positive MCF‐7 and triple negative MDA‐MB‐231 breast cancer cell lines. The preliminary cytotoxic screen, in the MCF‐7 cell line, revealed that the ligand (7‐chloro‐4‐(pyridin‐4‐yl)quinoline, L) and metallarectangle {Ir(μ‐Cl)(Cp*)}4(μ‐L)2(OTf)4 display superior activity to cisplatin, while {Ru(p‐cymene)}4(μ‐η2‐η2‐C2O4)2(μ‐L)2(OTf)4 was more potent than cisplatin in the triple‐negative MDA‐MD‐231 cell line. Upon evaluation in a multidose screen, ligand L and metallarectangle {Ir(μ‐Cl)(Cp*)}4(μ‐L)2(OTf)4 displayed antiproliferative activity almost two‐fold greater than cisplatin in the MCF‐7 cell line, while {Ru(p‐cymene)}4(μ‐η2‐η2‐C2O4)2(μ‐L)2(OTf)4 was over two‐times more active than cisplatin in the MDA‐MB‐231 cell line. Additionally, using the non‐tumorigenic MCF‐12 A breast epithelial cell line, the compounds demonstrate increased selectivity toward breast cancer cells over non‐tumorigenic cells. Furthermore, investigations into the interactions of ligand L and selected complexes with calf thymus DNA (CT‐DNA) and bovine serum albumin (BSA) indicate favourable binding.
From a different angle: We explored the incorporation of a quinolyl motif, ubiquitous to antimalarial chemotherapy, as part of PGM metallarectangles, intending to gain insight into the anticancer properties exemplified by this structure.
Ruthenium complexes containing triphenylphosphine diamide ligands were prepared, characterized, and tested for their biological activity against various cancer cell lines and the malaria parasite, ...Plasmodium falciparum. The effect of M (mono-substituted) and B (bis-substituted) complexes on the human cervical carcinoma (HeLa) cell line was investigated using the MTT assay. Five (B2, B3, B5, B6, and B13) of the 24 synthesized ruthenium complexes showed significant effects with IC50 values ranging between 0.3 and 2.3 μM. Evaluation of the potential biomolecular targets of B2 and B13 by fluorescence spectroscopy revealed relevant interactions with BSA and only a weak affinity for ctDNA. Complexes M2, B2, M13 and B13 were selected for further biological characterization. Their effect on the viability of two ovarian cancer cell lines was compared to normal cell lines, denoting their selectivity. Upon treatment of four different drug-resistant gynaecological cancer cell lines, differing in their multidrug-resistant phenotypes, the efficacy of the bis-substituted complexes was shown to be greater than their mono-substituted counterparts. The non-MDR cells are sensitive to all the tested complexes, compared to MDR cells which are less sensitive. Upon investigation of complexes M2, M13, B2, and B13 against sensitive and multidrug-resistant parasite strains of P. falciparum, the bis-substituted complexes were again shown to be the most potent, with submicromolar activity against both strains. Furthermore, the resistance indexes for the complexes were approximately equal to 1, which is at least 5-fold lower than chloroquine diphosphate, suggesting the ability of these complexes to retain their activity in resistant forms of the parasite.
Mono- and bis-substituted ruthenium complexes containing triphenylphosphine ligands were prepared, characterized, and tested for their biological activity against various cancer cell lines and the malaria parasite, Plasmodium falciparum. The complexes were also tested on multidrug-resistant cancer cell lines and multidrug-resistant plasmodium K1 strain and have shown relevant activities in both. Display omitted
•Ruthenium phosphine complexes show anti-cancer and anti-malarial activity in vitro.•Bis-substituted derivatives are more toxic then mono-derivatives.•The compounds exhibit a relevant degree of selectivity toward healthy cell lines.•Fluorescence spectroscopy reveals proteins as the likely target.•MDR cancer cells are more sensitive to investigated complexes then non-MDR cells.
Amodiaquine (AQ) is a potent antimalarial drug used in combination with artesunate as part of artemisinin-based combination therapies (ACTs) for malarial treatment. Due to the rising emergence of ...resistant malaria parasites, some of which have been reported for ACT, the usefulness of AQ as an efficacious therapeutic drug is threatened. Employing the organometallic hybridisation approach, which has been shown to restore the antimalarial activity of chloroquine in the form of an organometallic hybrid clinical candidate ferroquine (FQ), the present study utilises this strategy to modulate the biological performance of AQ by incorporating ferrocene. Presently, we have conceptualised ferrocenyl AQ derivatives and have developed facile, practical routes for their synthesis. A tailored library of AQ derivatives was assembled and their antimalarial activity evaluated against chemosensitive (NF54) and multidrug-resistant (K1) strains of the malaria parasite, Plasmodium falciparum. The compounds generally showed enhanced or comparable activities to those of the reference clinical drugs chloroquine and AQ, against both strains, with higher selectivity for the sensitive phenotype, mostly in the double-digit nanomolar IC50 range. Moreover, representative compounds from this series show the potential to block malaria transmission by inhibiting the growth of stage II/III and V gametocytes in vitro. Preliminary mechanistic insights also revealed hemozoin inhibition as a potential mode of action.
Display omitted
•Ferrocenyl derivatives of the clinical antimalarial drug, amodiaquine, have been prepared.•The lead compounds show enhanced/comparable nanomolar activity to both chloroquine and amodiaquine.•The lead compounds inhibit growth of stage II/III gametocytes.•Hemozoin inhibition is revealed as a potential mode of action.
Display omitted
•Luminescent nucleoside and nucleotide ester phenanthrenyl-GNA constituents were obtained and anticancer tested.•At 24 h treatment time, nucleoside acts mainly as a toxin and induces ...necrosis in HeLa cells. Nucleotide ester exhibits pro-apoptotic activity.•At 72h treatment time, nucleoside and gemcitabine hydrochloride, featured similar signs of anticancer activity.•Compounds were evaluated against P. falciparum strains. They showed low micromolar range activity and do not experience cross-resistance.
The knowledge pertaining to the chemistry and biological activity of glycol nucleic acid (GNA) components, like nucleosides and nucleotides, is still very limited. Herein we report on the preparation of the uracil nucleoside (1) and nucleotide ester GNA (2). The compounds are functionalised with a luminescent phenanthrenyl group. In DMSO, 1 and 2 are brightly fluorescent, with emission maxima at 390 nm, nanosecond decay times (0.6 and 0.75 ns, respectively), and quantum yields of ca. 0.2. In the solid phase, they show excimeric emission, with maxima at 495 nm (1) and 432 nm (2), and decay times of 3.7 ns (1) and 2.9 ns (2). The anticancer activity of the GNA components, as well as gemcitabine hydrochloride, used as a reference drug, were examined in vitro against human cancer HeLa and Ishikawa cells, as well as against normal L929 cells, using a battery of biochemical assays. Furthermore, biodistribution imaging studies were carried out in HeLa cells, with luminescence confocal microscopy, which showed that the compounds localized mainly in the lipophilic cellular compartments. Nucleoside (1) and nucleotide ester (2) features two different anticancer activity profiles. At 24 h of treatment, the nucleoside acts mainly as a toxin and induces necrosis in HeLa cells, whereas the nucleotide ester exhibits pro-apoptotic activity. At longer treatment times (72 h), the nucleoside and the reference, gemcitabine hydrochloride, featured almost identical signs of anticancer activity, such as S-phase cell cycle arrest, proliferation inhibition, and apoptosis induction. In view of this data, one can hypothesize that despite the structural differences, the newly obtained phenanthrenyl GNA nucleoside (1) and gemcitabine may share a common mechanism of anticancer activity in HeLa cancer cells. The GNA components were also examined as antiplasmodial agents against Plasmodium falciparum, in vitro. Nucleoside (1) was found to be more potent than nucleotide (2), displaying activity in the low micromolar range. Furthermore, both phenanthrene derivatives were found to display resistance indices at least 9-fold lower than chloroquine diphosphate (CQDP).
Abstract Introduction Hypertrophic scar (HTS) remains a comorbidity of burn injury, often requiring split thickness skin grafting (STSG) and resulting in symptomatic HTS at grafted sites and STSG ...donor sites (DS). Literature supports the use of ablative fractional CO2 laser (FLSR) to treat HTS, however many trials lack control sites and tissue-level examinations. Given the widespread adoption of FLSR for HTS, delegation of non-treated scar sites for the sake of RCT is troubling for many clinicians. We trialed using STSG DS scars for randomization rather than withholding FLSR from HTS at grafted sites. Methods Patients (n=25) were treated for DS scar with FLSR. DS scars were randomized and treated with either 5 FLSR treatments, follow-ups, and standard of care (SOC) or SOC only. Prior to treatment, DS skin and normal skin (NS) were evaluated for trans-epidermal water loss (TEWL), melanin index (MI), elasticity, and erythema. Serial biopsies were analyzed for epidermal thickness, rete ridge ratio (RRR), and papillary dermal cellularity. All sites, including a separate STSG scar site, were evaluated using the patient and observer scar assessment scale (POSAS) and Vancouver Scar Scale (VSS). Results Prior to treatment, DS skin had increased TEWL (10.5±0.8 vs 8.3±0.5 g/m2h, n=18; p=0.03), decreased RRR (1.1±0.0 vs 1.3±0.1, n=16; p=0.0001), and increased cellularity (8.8±0.9% vs 4.9 ± 0.6%, n=17; p=0.0014) compared to NS. DS skin and NS were not different in MI (p=0.07), erythema (p=0.77), elasticity (p=0.06), or epidermal thickness (p=0.32). Over time, control site DS and laser-treated DS were not different in TEWL (p=0.92), elasticity (p=0.45), erythema (p=0.99), RRR (0.97), cellularity (0.99), MI, epidermal thickness, POSAS-O score, POSAS-P score, or VSS (p>0.99). Over time, burn scar had increased skin elasticity (172.0±15.5 vs 78.5±13.2 N/m, n=17; p=0.0065). Burn scar did change in TEWL (p=0.53), MI (p=0.24), erythema (p=0.99), POSAS-O score (p=0.78), POSAS-P score (p=0.13), or VSS (p>0.99) over time. Conclusions NS and DS skin possess inherent physiological differences, though not to the degree of STSG HTS vs. NS. FLSR may not alter the rate of maturation and remodeling of DS scar compared to current SOC. While improvement in scar assessment was observed in laser-treated STSG HTS, no specific control for these sites was analyzed. Due to differences in pathophysiology of HTS formation at STSG sites and DS, DS may not be an adequate substitute for STSG HTS when designing RCTs to evaluate the effect of FLSR. Applicability of Research to Practice Prior studies evaluating the use FLSR consist of low-powered clinical trials or case studies without control sites or tissue level examinations, prompting the design of a RCT in DS scars. However, this scar type may not be suitable for this study design. Future work should extend to extra-cellular matrix morphology and transcriptomics of donor site and burn scar healing to better understand the effects of laser treatment.
PDF
