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Chemistry (Weinheim An Der Bergstrasse,... Nov 2023Stimuli-responsive fluorogenic prodrugs are advantageous for the targeted drug delivery enabling real-time non-invasive monitoring with turn-on fluorescence. We report...
Stimuli-responsive fluorogenic prodrugs are advantageous for the targeted drug delivery enabling real-time non-invasive monitoring with turn-on fluorescence. We report herein the dual-stimuli (ROS and CA)-responsive thiocarbamate-based prodrug (AM-TCB) for the turn-on fluorogenic delivery of the naphthalimide-based anticancer agent amonafide along with the gasotransmitter hydrogen sulfide (H S). A carbamate-based prodrug AM-CB was also designed, capable of releasing the anticancer agent amonafide without any H S. The prodrugs were synthesized using multi-step organic synthesis. UV-Vis and fluorescence spectroscopic studies revealed selective reactivity of the boronate ester group of prodrugs towards ROS (primarily H O ) with the release of amonafide and COS/CO via self-immolative processes. Hydrolysis of the generated COS by carbonic anhydrase (CA) produces H S. While the prodrug AM-TCB retained the anticancer activity of free amonafide in cancer cells (MDA-MB-231 and HeLa), unlike amonafide, it enhanced the cellular viability of the non-malignant cells (HEK-293). Fluorescence imaging in HeLa cells revealed the simultaneous delivery of the anticancer agent and H S from AM-TCB with turn-on fluorescence. Western blot studies further revealed the cytoprotective effects of the released H S from AM-TCB. The present adjuvant strategy therefore would be helpful in future for ameliorating the anticancer drug-induced side-effects.
Topics: Humans; Prodrugs; Hydrogen Sulfide; HeLa Cells; Fluorescence; Reactive Oxygen Species; HEK293 Cells; Antineoplastic Agents
PubMed: 37665099
DOI: 10.1002/chem.202302197 -
Theranostics 2015Magnetic resonance imaging (MRI)-visible amonafide-eluting alginate microspheres were developed for targeted arterial-infusion chemotherapy. These alginate microspheres...
Magnetic resonance imaging (MRI)-visible amonafide-eluting alginate microspheres were developed for targeted arterial-infusion chemotherapy. These alginate microspheres were synthesized using a highly efficient microfluidic gelation process. The microspheres included magnetic clusters formed by USPIO nanoparticles to permit MRI and a sustained drug-release profile. The biocompatibility, MR imaging properties and amonafide release kinetics of these microspheres were investigated during in vitro studies. A xenograft rodent model was used to demonstrate the feasibility to deliver these microspheres to liver tumors using hepatic transcatheter intra-arterial infusions and potential to visualize the intra-hepatic delivery of these microspheres to both liver tumor and normal tissues with MRI immediately after infusion. This approach offer the potential for catheter-directed drug delivery to liver tumors for reduced systemic toxicity and superior therapeutic outcomes.
Topics: Adenine; Alginates; Animals; Antineoplastic Agents; Disease Models, Animal; Drug Carriers; Glucuronic Acid; Hexuronic Acids; Injections, Intra-Arterial; Liver Neoplasms; Magnetic Resonance Imaging; Microspheres; Naphthalimides; Organophosphonates; Rats
PubMed: 25767615
DOI: 10.7150/thno.10823 -
ACS Applied Materials & Interfaces Dec 2021Nanosizing has emerged as one of the most effective formulation strategies for enhancement of dissolution properties of active pharmaceutical ingredients (APIs). In...
Nanosizing has emerged as one of the most effective formulation strategies for enhancement of dissolution properties of active pharmaceutical ingredients (APIs). In addition to enhancing the specific area of the dissolving solids, nanosizing can also capture and stabilize the metastable form of the API, which can further enhance the solubility by drastic modulation of surface energies. Herein, we employ meniscus-guided coating to fabricate nanothin films of three APIs that show anticancer properties and are poorly soluble:10-HCPT, SN-38, and amonafide. By modulating the coating speed, we systematically deposited the APIs in films ranging from ∼200 nm thickness to extreme confinement of ∼10 nm (<10 molecular layers). In all three APIs, we observe a general order-to-disorder transition with semicrystalline (10-HCPT and amonafide) or amorphous (SN-38) form of API solids trapped in thin films when the thickness decreases below a critical value of ∼25-30 nm. The existence of a critical thickness highlights the importance of nanoconfinement in tuning molecular packing. In the case of 10-HCPT, we demonstrate that the disordered form of the API occurs largely due to lack of incorporation of water molecules in thinner films below the critical thickness, thereby disrupting the three-dimensional hydrogen-bonded network held by water molecules. We further developed a dissolution model that predicts variation of the intrinsic dissolution rate (IDR) with API film thickness, which also closely matched with experimental results. We achieved drastic improvement in the IDR of ∼240% in 10-HCPT by decreasing film thickness alone. Further leveraging the order-to-disorder transition led to 2570% modulation of the IDR for amonafide. Our work demonstrates, for the first time, opportunities to largely modulate API dissolution by precisely controlling the dimensionality of thin films.
Topics: Adenine; Coated Materials, Biocompatible; Humans; Irinotecan; Microscopy, Atomic Force; Molecular Structure; Nanoparticles; Organophosphonates; Particle Size; Surface Properties; X-Ray Diffraction
PubMed: 34783517
DOI: 10.1021/acsami.1c08398 -
European Journal of Medicinal Chemistry Jan 2018A new class of polyamine analogues modified by alkylation at the terminal of the polyamine chain has been synthesized and their structures were determined by H NMR, C...
A new class of polyamine analogues modified by alkylation at the terminal of the polyamine chain has been synthesized and their structures were determined by H NMR, C NMR, ESI-MS and elemental analysis. As the representative compound, 3f displayed a broad spectrum of anti-cancer effects by MTT assays. Tumor xenograft model and pulmonary metastasis model showed that compound 3f significantly suppressed tumor growth and metastasis in vivo, which was more stronger than the reference drug amonafide. Molecular mechanisms indicated that compound 3f exhibited antiproliferative activities and induced the generation of reactive oxygen species (ROS), which resulted in the occurrence of autophagy. The downregulated expression of MMP-9 and β-catenin by compound 3f accounted for the inhibition of migration. Taken altogether, the in vitro and in vivo biological evaluations corroborated compound 3f to be an effective anticancer agent.
Topics: Alkylation; Animals; Antineoplastic Agents; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Male; Mice; Molecular Structure; Neoplasms, Experimental; Polyamines; Structure-Activity Relationship; Tumor Cells, Cultured
PubMed: 29133040
DOI: 10.1016/j.ejmech.2017.10.069 -
Journal of Inorganic Biochemistry Jun 2021A series of tripodal ferrocenyl bis-naphthalimide derivatives were synthesized and characterized. All of the bis-naphthalimide derivatives exhibited good DNA binding...
A series of tripodal ferrocenyl bis-naphthalimide derivatives were synthesized and characterized. All of the bis-naphthalimide derivatives exhibited good DNA binding ability which was confirmed by ethidium bromide (EB) displacement experiment and ultraviolet (UV)-visible absorption titration. And the binding mode of these compounds was proved to be a hybrid binding mode by experiments. The cytotoxicity of synthesized compounds against 4 different human cancer cell lines (EC109, BGC823, SGC7901 and HEPG2) was evaluated by thiazolyl blue tetrazolium bromide (MTT) assay. All of the bis-naphthalimide derivatives exhibited good anticancer activity than the positive control drug (amonafide), which was due to the promotion of reactive oxygen species (ROS) level in test cancer cells by the reversible one-electron redox process of ferrocenyl bis-naphthalimide derivatives. Although there was no obvious relationship between the binding constants and the chain length, the structure cytotoxicity relationship revealed that the linker of n = 3, m = 1 was the best choice for the tested tripodol bis-naphthalimide derivatives. SYNOPSIS: A series of tripodal ferrocenyl bis-naphthalimide derivatives were synthesized to study the DNA binding ability and the cytotoxicity induced by reactive oxygen species. All of the compounds exhibited good DNA binding ability. And the structure cytotoxicity relationship revealed that the structure of 5h was the best choice.
Topics: Adenine; Antineoplastic Agents; Cell Line, Tumor; DNA; Drug Screening Assays, Antitumor; Electrochemistry; Ethidium; Ferrous Compounds; Flow Cytometry; Humans; Metallocenes; Molecular Structure; Naphthalimides; Organophosphonates; Reactive Oxygen Species; Structure-Activity Relationship
PubMed: 33831713
DOI: 10.1016/j.jinorgbio.2021.111425 -
Molecules (Basel, Switzerland) Oct 2016A novel series of diethyl {4-[(5-substituted-1,3-dioxo-1-benzo[]isoquinolin-2(3)-yl)-methyl]-1-1,2,3-triazol-1-yl}alkylphosphonates designed as analogues of amonafide...
A novel series of diethyl {4-[(5-substituted-1,3-dioxo-1-benzo[]isoquinolin-2(3)-yl)-methyl]-1-1,2,3-triazol-1-yl}alkylphosphonates designed as analogues of amonafide was synthesized. All phosphonates were assessed for antiviral activity against a broad range of DNA and RNA viruses and several of them showed potency against varicella-zoster virus (VZV) [EC (50% effective concentration) = 27.6-91.5 μM]. Compound exhibited the highest activity against a thymidine kinase-deficient (TK) VZV strain (EC = 27.59 μM), while was the most potent towards TK⁺ VZV (EC = 29.91 μM). Cytostatic properties of the compounds --- were studied on L1210, CEM, HeLa and HMEC-1 cell lines and most of them were slightly cytostatic for HeLa [IC (50% inhibitory concentration) = 29-130 µM] and L1210 cells [IC (50% inhibitory concentration) = 14-142 µM].
Topics: Adenine; Antiviral Agents; Cell Line; Cell Proliferation; Cytostatic Agents; HeLa Cells; Herpesvirus 3, Human; Humans; Inhibitory Concentration 50; Molecular Structure; Naphthalimides; Organophosphonates
PubMed: 27792200
DOI: 10.3390/molecules21111420 -
Anti-cancer Agents in Medicinal... 2024The efficacy of drugs against cancer in clinical settings may be limited due to pharmacokinetic issues, side effects and the emergence of drug resistance. However, a...
The efficacy of drugs against cancer in clinical settings may be limited due to pharmacokinetic issues, side effects and the emergence of drug resistance. However, a class of anticancer drugs known as naphthalimides have proven to be very effective. These derivatives have demonstrated to be effective in treating different types of cancers and exhibit strong DNA binding affinity. The anticancer properties of the naphthalimide derivatives allow them to target a number of cancer cell lines. Researchers have investigated the anticancer activity of numerous naphthalimide derivatives, such as heterocyclic fused, non-fused substituted, metal-substituted and carboxamide derivatives. Surprisingly, some derivatives demonstrate greater activity than the reference norms, such as cisplatin, amonafide, mitonafide and others and are selective against many cell lines. The primary objective of this research is to comprehend the effects of various substitution patterns on the structure-activity relationship (SAR) of these derivatives and the instances in which they enhance or reduce this biological activity.
Topics: Humans; Naphthalimides; Structure-Activity Relationship; Antineoplastic Agents; Cell Line, Tumor; Cisplatin
PubMed: 37974443
DOI: 10.2174/0118715206274007231107094411 -
Bioorganic & Medicinal Chemistry Jul 2015DNA intercalators are commonly used as anti-cancer and anti-tumor agents. As a result, it is imperative to understand how changes in intercalator structure affect...
DNA intercalators are commonly used as anti-cancer and anti-tumor agents. As a result, it is imperative to understand how changes in intercalator structure affect binding affinity to DNA. Amonafide and mitonafide, two naphthalimide derivatives that are active against HeLa and KB cells in vitro, were previously shown to intercalate into DNA. Here, a systematic study was undertaken to change the 3-substituent on the aromatic intercalator 1,8-naphthalimide to determine how 11 different functional groups with a variety of physical and electronic properties affect binding of the naphthalimide to DNA and RNA duplexes of different sequence compositions and lengths. Wavelength scans, NMR titrations, and circular dichroism were used to investigate the binding mode of 1,8-naphthalimide derivatives to short synthetic DNA. Optical melting experiments were used to measure the change in melting temperature of the DNA and RNA duplexes due to intercalation, which ranged from 0 to 19.4°C. Thermal stabilities were affected by changing the substituent, and several patterns and idiosyncrasies were identified. By systematically varying the 3-substituent, the binding strength of the same derivative to various DNA and RNA duplexes was compared. The binding strength of different derivatives to the same DNA and RNA sequences was also compared. The results of these comparisons shed light on the complexities of site specificity and binding strength in DNA-intercalator complexes. For example, the consequences of adding a 5'-TpG-3' or 5'-GpT-3' step to a duplex is dependent on the sequence composition of the duplex. When added to a poly-AT duplex, naphthalimide binding was enhanced by 5.6-11.5°C, but when added to a poly-GC duplex, naphthalimide binding was diminished by 3.2-6.9°C.
Topics: Antineoplastic Agents; Base Sequence; DNA; Intercalating Agents; Molecular Sequence Data; Naphthalimides; Nucleic Acid Conformation; Nucleic Acid Denaturation; Nucleotides; RNA; Structure-Activity Relationship; Temperature; Thermodynamics
PubMed: 25960324
DOI: 10.1016/j.bmc.2015.04.030 -
Chemical Communications (Cambridge,... Feb 2021We developed an activatable molecular reagent, PNF, triggered by intracellular H2S in the lysosome to release the therapeutic drug amonafide, which can escape from the...
We developed an activatable molecular reagent, PNF, triggered by intracellular H2S in the lysosome to release the therapeutic drug amonafide, which can escape from the lysosome into the nucleus to induce autophagy of cancer cells. PNF exhibits potent inhibitory activity against cisplatin-resistant tumor cell lines.
Topics: Antineoplastic Agents; Cell Line, Tumor; Humans; Hydrogen Sulfide
PubMed: 33496706
DOI: 10.1039/d0cc07982k -
West African Journal of Medicine Aug 2023Maternal anaemia results in morbidity and mortality in both the mother and the unborn child.
BACKGROUND
Maternal anaemia results in morbidity and mortality in both the mother and the unborn child.
INTRODUCTION
Several factors have been found to determine anaemia among pregnant women but vary from place to place depending on the population and setting of the study. We thus set out to determine predictors of anaemia among pregnant women at booking in FMC, Bida.
METHODS
This is a descriptive cross-sectional study carried out over a period of three (3) months among 248 pregnant women booking for Antenatal Care (ANC) at the ANC Clinic of the Federal Medical Centre (FMC), Bida, Niger state.
RESULTS
The mean haemoglobin concentration was 10.2 ±1.0g/dl and 72.6% of all the women were anaemic (haemoglobin concentration < 11g/dl). Anaemia was significantly related to Religion (Islam) (p <0.001), Ethnicity (Yoruba) (p <0.001), the Gestational age (second trimester) at booking (p= 0.013), Interpregnancy interval (< 2 years) (p <0.001), microcytic red blood cell (p <0.001) and hypochromic red blood cell (p <0.001) morphology and absence of fever (p = 0.043) in index pregnancy. In the final analysis at the multivariate level hypochromic red blood cells (OR = 0.049, p = 0.001, CI = 0.008-0.307), Gestational age (second trimester) at booking (OR = 3.465, p = 0.011, CI = 1.323-9.077) and Religion (Islam) (OR = 4.309, p = 0.006, CI = 1.520-12.215) remained significant independent predictors of anaemia.
CONCLUSION
Anaemia in pregnancy is still a frequent finding, and it's linked to diets poor in iron and folate, booking in the second trimester, and religion. The prevalence and severity of anaemia in pregnancy will be considerably reduced by early booking, and iron/folate nutritional interventions.
Topics: Pregnancy; Female; Humans; Prenatal Care; Pregnant Women; Nigeria; Cross-Sectional Studies; Niger; Anemia; Folic Acid; Iron; Hemoglobins
PubMed: 37639388
DOI: No ID Found