Cysteine-responsive prodrug of the anti-cancer drug amonafide: fluorogenic adjuvant drug delivery with hydrogen sulfide (H<sub>2</sub>S)

Bhabak, Krishna P.; Mahato, Sulendar K; Barman, Pallavi; Badirujjaman, Md

doi:10.1039/d3cc00220a

Cited by 8 publications

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“…In early 2023, our group reported the first example of cysteine-triggered prodrug AM-ITC for the delivery of amonafide and H 2 S with turn-on fluorescence (Scheme 1A). [12] However, due to very high electrophilicity of the isothiocyanate group, the drug release profile was found to be quite rapid. Moreover, due to the participation of two competitive pathways for Cys-triggered drug uncaging process, only a partial release of both amonafide and H 2 S could be achieved from the prodrug.…”

Section: Introductionmentioning

confidence: 99%

Dual‐Stimuli‐Activatable Hybrid Prodrug for the Self‐Immolative Delivery of an Anticancer Agent and Hydrogen Sulfide with Turn‐On Fluorescence

Sufian,

Badirujjaman,

Barman

et al. 2023

Chemistry A European J

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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 (H2S). A carbamate‐based prodrug AM‐CB was also designed, capable of releasing the anticancer agent amonafide without any H2S. 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 H2O2) with the release of amonafide and COS/CO2 via self‐immolative processes. Hydrolysis of the generated COS by carbonic anhydrase (CA) produces H2S. 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 H2S from AM‐TCB with turn‐on fluorescence. Western blot studies further revealed the cytoprotective effects of the released H2S from AM‐TCB. The present adjuvant strategy therefore would be helpful in future for ameliorating the anticancer drug‐induced side‐effects.

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Section: Introductionmentioning

confidence: 99%

Dual‐Stimuli‐Activatable Hybrid Prodrug for the Self‐Immolative Delivery of an Anticancer Agent and Hydrogen Sulfide with Turn‐On Fluorescence

Sufian,

Badirujjaman,

Barman

et al. 2023

Chemistry A European J

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Esterase‐Responsive Self‐Immolative Prodrugs for the Sustained Delivery of the Anticancer Drug 5‐Fluorouracil with Turn‐On Fluorescence

Badirujjaman,

Thummer,

Bhabak

2024

Chemistry An Asian Journal

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Stimuli‐responsive prodrugs of anticancer drugs are advantageous for the selective delivery of drugs to cancer cells with minimized off‐target side effects. In the present study, esterase‐activatable fluorogenic prodrugs of the chemotherapeutic drug 5‐fluorouracil (5‐FU) have been rationally designed and synthesized using multi‐step organic synthesis. While 5‐FU was connected directly with the fluorophore via a C‐N bond in the prodrug BJ‐50, an additional self‐immolative benzylic spacer with a carbonate linker was incorporated in the prodrug BJ‐92. Although absorption and emission spectroscopic studies revealed the activation of both the prodrugs by porcine liver esterase (PLE), reverse‐phase HPLC studies confirmed the inability of BJ‐50 to release the active drug 5‐FU. In contrast, a sustained release of 5‐FU and Cou‐OH was observed from BJ‐92 in the presence of PLE. The endogenous esterase‐mediated activation of the prodrug BJ‐92 was validated by the turn‐on fluorescence in HeLa cells and the anti‐proliferative activities in A549, HeLa, and HEK‐293 cells. Modulation of the expression of a few cancer marker proteins by BJ‐92 and 5‐FU was studied to evaluate their anticancer activities. As esterases are overexpressed in cancer cells, the prodrug in the present study would be helpful in selectively delivering 5‐FU to cancer cells with reduced off‐target side‐effects.

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Research Progress in the Field of Hydrogen Sulfide Donors in the Last Five Years

Pang,

Huo,

Yin

2024

ChemBioChem

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Hydrogen sulfide (H2S) serves as the third gasotransmitter, crucial in various physiological processes involving its production and metabolism. Elevated levels of H2S can result in acute or chronic poisoning, whereas lower concentrations are involved in regulating diverse physiological and pathological activities within the human body. Moreover, it actively participates in maintaining normal cellular function by exerting cell protection and anti‐apoptotic effects. In recent years, extensive research has been conducted to explore the physiological significance of H2S and its potential applications in developing prodrugs. To further unravel the biological and clinical potential of H2S, H2S donors have gained widespread utilization. These compounds facilitate our understanding of the specific functional aspects governed by H2S and hold promise as potential therapeutic agents. Therefore, it is necessary to study H2S as a delivery vehicle at the cellular and in vivo levels. This review provides an overview of advancements made over the past five years regarding H2S donors and their applications in biology, encompassing indirectly released donors of carbonyl sulfide (COS), directly released small molecule donors, Nanocomposite scaffolds, and hydrogels.

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Cysteine-responsive prodrug of the anti-cancer drug amonafide: fluorogenic adjuvant drug delivery with hydrogen sulfide (H₂S)

Abstract: L-cysteine (Cys)-responsive turn-on fluorogenic prodrug AM-ITC was developed for the adjuvant delivery of the anti-cancer drug amonafide and the gasotransmitter hydrogen sulfide (H2S) in aqueous and cellular medium. Considering the...

Cited by 8 publications

References 39 publications

Dual‐Stimuli‐Activatable Hybrid Prodrug for the Self‐Immolative Delivery of an Anticancer Agent and Hydrogen Sulfide with Turn‐On Fluorescence

Dual‐Stimuli‐Activatable Hybrid Prodrug for the Self‐Immolative Delivery of an Anticancer Agent and Hydrogen Sulfide with Turn‐On Fluorescence

Esterase‐Responsive Self‐Immolative Prodrugs for the Sustained Delivery of the Anticancer Drug 5‐Fluorouracil with Turn‐On Fluorescence

Research Progress in the Field of Hydrogen Sulfide Donors in the Last Five Years

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Cysteine-responsive prodrug of the anti-cancer drug amonafide: fluorogenic adjuvant drug delivery with hydrogen sulfide (H2S)

Abstract: L-cysteine (Cys)-responsive turn-on fluorogenic prodrug AM-ITC was developed for the adjuvant delivery of the anti-cancer drug amonafide and the gasotransmitter hydrogen sulfide (H2S) in aqueous and cellular medium. Considering the...

Cited by 8 publications

References 39 publications

Dual‐Stimuli‐Activatable Hybrid Prodrug for the Self‐Immolative Delivery of an Anticancer Agent and Hydrogen Sulfide with Turn‐On Fluorescence

Dual‐Stimuli‐Activatable Hybrid Prodrug for the Self‐Immolative Delivery of an Anticancer Agent and Hydrogen Sulfide with Turn‐On Fluorescence

Esterase‐Responsive Self‐Immolative Prodrugs for the Sustained Delivery of the Anticancer Drug 5‐Fluorouracil with Turn‐On Fluorescence

Research Progress in the Field of Hydrogen Sulfide Donors in the Last Five Years

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Cysteine-responsive prodrug of the anti-cancer drug amonafide: fluorogenic adjuvant drug delivery with hydrogen sulfide (H₂S)