Anti-aging effects of chlorpropamide depend on mitochondrial complex-II and the production of mitochondrial reactive oxygen species

Mao, Zhifan; Liu, Wenwen; Huang, Yunyuan; Sun, Tianyue; Bao, Keting; Feng, Jiali; Moskalev, Alexey; Hu, Zheyi; Li, Jian

doi:10.1016/j.apsb.2021.08.007

Cited by 7 publications

(8 citation statements)

References 67 publications

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“…Finally, 10 drugs which showed up to 10% increase in mean lifespan extension were chosen for the third screening with 60 worms per concentration (400 μM, 100 μM, and 25 μM), respectively ( Figure 1—source data 2 ). Apart from recently reported verapamil hydrochloride ( Liu et al, 2020 ) and chlorpropamide ( Mao et al, 2022 ) listed in our screening results, crotamiton was finally selected as one hit compound with significant effect on C. elegans lifespan extension in this study (p < 0.01) ( Figure 1a ). The distribution of approved drugs combinations per disease area in this phenotypic screening study was showed in Figure 1b .…”

Section: Resultsmentioning

confidence: 99%

Crotamiton derivative JM03 extends lifespan and improves oxidative and hypertonic stress resistance in Caenorhabditis elegans via inhibiting OSM-9

Bao

Liu

Song

et al. 2022

eLife

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While screening our in-house 1072 marketed drugs for their ability to extend the lifespan using Caenorhabditis elegans (C. elegans) as an animal model, crotamiton (N-ethyl-o-crotonotoluidide) showed anti-aging activity and was selected for further structural optimization. After replacing the ortho-methyl of crotamiton with ortho-fluoro, crotamiton derivative JM03 was obtained and showed better activity in terms of lifespan-extension and stress resistance than crotamiton. It was further explored that JM03 extended the lifespan of C. elegans through osmotic avoidance abnormal-9 (OSM-9). Besides, JM03 improves the ability of nematode to resist oxidative stress and hypertonic stress through OSM-9, but not osm-9/capsaicin receptor related-2 (OCR-2). Then the inhibition of OSM-9 by JM03 reduces the aggregation of Q35 in C. elegans via upregulating the genes associated with proteostasis. SKN-1 signaling was also found to be activated after JM03 treatment, which might contribute to proteostasis, stress resistance and lifespan extension. In summary, this study explored a new small molecule derived from crotamiton, which has efficient anti-oxidative, anti-hypertonic, and anti-aging effects, and could further lead to promising application prospects.

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Section: Resultsmentioning

confidence: 99%

Crotamiton derivative JM03 extends lifespan and improves oxidative and hypertonic stress resistance in Caenorhabditis elegans via inhibiting OSM-9

Bao

Liu

Song

et al. 2022

eLife

Self Cite

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show abstract

“…Finally, 10 drugs which showed up to 10% increase in mean lifespan extension were chosen for the third screening with 60 worms per concentration (400 μM, 100 μM and 25 μM), respectively (Figure 1-source data 2). Apart from recently reported verapamil hydrochloride 21 and chlorpropamide 22 listed in our screening results, crotamiton was finally selected as one hit compound with significant effect on C. elegans lifespan extension in this study (P < 0.01) (Fig. 1a).…”

Section: Crotamiton Prolongs Lifespan Of C Elegansmentioning

confidence: 99%

Crotamiton derivative JM03 extends lifespan and improves oxidative and hypertonic stress resistance in Caenorhabditis elegans via inhibiting OSM-9

Bao

Feng

Liu

et al. 2021

Preprint

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While screening our in-house 1,072 marketed drugs for their ability to extend the lifespan using Caenorhabditis elegans (C. elegans) as an animal model, crotamiton (N-ethyl-o-crotonotoluidide) showed anti-aging activity and was selected for further structural optimization. After replacing the ortho-methyl of crotamiton with ortho-fluoro, crotamiton derivative JM03 was obtained and showed better activity in terms of lifespan-extension and stress resistance than crotamiton. It was further explored that JM03 extended the lifespan of C. elegans through osmotic avoidance abnormal-9 (OSM-9). Besides, JM03 improves the ability of nematode to resist oxidative stress and hypertonic stress through OSM-9, but not osm-9/capsaicin receptor related-2 (OCR-2). Then the inhibition of OSM-9 by JM03 reduces the aggregation of Q35 in C. elegans via upregulating the genes associated with proteostasis. SKN-1 signaling was also found to be activated after JM03 treatment, which might contribute to proteostasis, stress resistance and lifespan extension. In summary, this study explored a new small molecule derived from crotamiton, which has efficient anti-oxidative, anti-hypertonic and anti-aging effects, and could further lead to promising application prospects.

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“…In this regard, a class of ureas—sulfonylureas (SUs)—have long been used as antidiabetic agents and impact a range of biological pathways. 3 − 6 They are reported to have anti-aging properties 7 and are proposed as an auxiliary therapy for Alzheimer’s disease. 8 They have a role in ameliorating inflammatory pathways by acting as inflammasome inhibitors.…”

Section: Introductionmentioning

confidence: 99%

“…Synthetic innovation can steer the exploration of new chemical space around under-utilized scaffolds to expand their potential further in biochemical applications. In this regard, a class of ureassulfonylureas (SUs)have long been used as antidiabetic agents and impact a range of biological pathways. − They are reported to have anti-aging properties and are proposed as an auxiliary therapy for Alzheimer’s disease . They have a role in ameliorating inflammatory pathways by acting as inflammasome inhibitors. , They can also act as potassium ATP channel modulators and ACAT inhibitors .…”

Section: Introductionmentioning

confidence: 99%

One-Pot Synthesis of Thio-Augmented Sulfonylureas via a Modified Bunte’s Reaction

et al. 2022

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We report the development of a one-pot Bunte’s reaction-enabled expeditious platform under aqueous conditions for the scalable conversion of sulfonylureas to synthetically versatile thio-sulfonylureas. The reaction was further propagated in the same pot to yield diverse chiral and achiral isothiosulfonyl analogs. The protocol enabled the synthesis of various drug-like molecules and was applied to an enantiomeric synthesis of a cannabinoid receptor antagonist SLV326.

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Anti-aging effects of chlorpropamide depend on mitochondrial complex-II and the production of mitochondrial reactive oxygen species

Cited by 7 publications

References 67 publications

Crotamiton derivative JM03 extends lifespan and improves oxidative and hypertonic stress resistance in Caenorhabditis elegans via inhibiting OSM-9

Crotamiton derivative JM03 extends lifespan and improves oxidative and hypertonic stress resistance in Caenorhabditis elegans via inhibiting OSM-9

Crotamiton derivative JM03 extends lifespan and improves oxidative and hypertonic stress resistance in Caenorhabditis elegans via inhibiting OSM-9

One-Pot Synthesis of Thio-Augmented Sulfonylureas via a Modified Bunte’s Reaction

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