A thalidomide–hydroxyurea hybrid increases HbF production in sickle cell mice and reduces the release of proinflammatory cytokines in cultured monocytes

Lanaro, Carolina; Franco‐Penteado, Carla F.; Silva, Fábio H.; Fertrin, Kleber Yotsumoto; Santos, Jean Leandro dos; Wade, Marlene; Yerigenahally, Shobha; Melo, Thais R. de; Chin, Chung Man; Kutlar, Abdullah; Meiler, Steffen E.; Costa, Fernando Ferreira

doi:10.1016/j.exphem.2017.10.003

Cited by 11 publications

(8 citation statements)

References 24 publications

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“…One promising approach for treating SCD is to induce HbF, which does not polymerize, thus preventing hemoglobin polymerization (Sankaran, 2011;Ware et al, 2017). Chelucci et al (2019) promising SCD treatment (Lanaro et al, 2018). Melo et al (2018) reported seven new phthalimide-furoxan conjugates (157-163) (Figure 13), and all the compounds were assessed for their antiplatelet properties.…”

Section: Phthalimides As Fetal Hemoglobin (Hbf) Inducersmentioning

confidence: 99%

“…In terms of TNF‐α inhibition, compounds 148 and 156 demonstrated the highest inhibition values (Chelucci et al, 2019). Lanaro et al (2018) reported on a phthalimide‐based analog containing the hydroxyurea moiety ( 146 ) and its effects on HbF production and proinflammatory profiles in sickle cell animal models (Figure 12). Compound 146 increased HbF protein levels by 53% compared to the vehicle and exhibited anti‐inflammatory properties by reducing the production of inflammatory cytokines in monocyte cultures from SCA mice.…”

Section: Phthalimides As Fetal Hemoglobin (Hbf) Inducersmentioning

confidence: 99%

“…Compound 146 increased HbF protein levels by 53% compared to the vehicle and exhibited anti‐inflammatory properties by reducing the production of inflammatory cytokines in monocyte cultures from SCA mice. Compared to hydroxyurea and dexamethasone, compound 146 exhibited lower values for proinflammatory levels, indicating its potential as a promising SCD treatment (Lanaro et al, 2018).…”

Section: Phthalimides As Fetal Hemoglobin (Hbf) Inducersmentioning

confidence: 99%

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Phthalimide as a versatile pharmacophore scaffold: Unlocking its diverse biological activities

Fernandes

Lopes

Santos

et al. 2023

Drug Development Research

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Phthalimide, a pharmacophore exhibiting diverse biological activities, holds a prominent position in medicinal chemistry. In recent decades, numerous derivatives of phthalimide have been synthesized and extensively studied for their therapeutic potential across a wide range of health conditions. This comprehensive review highlights the latest developments in medicinal chemistry, specifically focusing on phthalimide‐based compounds that have emerged within the last decade. These compounds showcase promising biological activities, including anti‐inflammatory, anti‐Alzheimer, antiepileptic, antischizophrenia, antiplatelet, anticancer, antibacterial, antifungal, antimycobacterial, antiparasitic, anthelmintic, antiviral, and antidiabetic properties. The physicochemical profiles of the phthalimide derivatives were carefully analyzed using the online platform pkCSM, revealing the remarkable versatility of this scaffold. Therefore, this review emphasizes the potential of phthalimide as a valuable scaffold for the development of novel therapeutic agents, providing avenues for the exploration and design of new compounds.

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Section: Phthalimides As Fetal Hemoglobin (Hbf) Inducersmentioning

confidence: 99%

Section: Phthalimides As Fetal Hemoglobin (Hbf) Inducersmentioning

confidence: 99%

Section: Phthalimides As Fetal Hemoglobin (Hbf) Inducersmentioning

confidence: 99%

See 1 more Smart Citation

Phthalimide as a versatile pharmacophore scaffold: Unlocking its diverse biological activities

Fernandes

Lopes

Santos

et al. 2023

Drug Development Research

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“…Finally, metformin, a FOXO3 inducer, has been shown to increase HbF production in erythroid cells in vitro , and is now being tested in patients with SCD (NCT02981329). Other promising HbF reactivating agents currently in preclinical studies include recombinant SIRT1 64 , a hydroxyurea-thalidomide hybrid, 65 resveratrol, 66 and dimethyl fumarate. 67…”

Section: [H1] Developing New Scd Therapiesmentioning

confidence: 99%

Therapeutic strategies for sickle cell disease: towards a multi-agent approach

Telen

Malik

Vercellotti

2018

Nat Rev Drug Discov

144

107

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For over 100 years, clinicians and scientists have been unraveling the consequences of the A to T substitution in the beta globin gene that produces hemoglobin S, which leads to the systemic manifestations of sickle cell disease (SCD), including vaso-occlusion, anemia, hemolysis, organ injury and pain. However, despite growing understanding of the mechanisms of hemoglobin S polymerization and its effects on red blood cells, only two therapies for SCD — hydroxyurea and L-glutamine — are approved by the US Food and Drug Administration. Moreover, these treatment options do not fully address the manifestations of SCD. The pathophysiology of SCD suggests a complex network of interdependent processes, and in this article, we review efforts to develop new drugs targeting these processes, including agents that reactivate fetal hemoglobin, anti-sickling agents, anti-adhesive agents, modulators of inflammation, ischemia/reperfusion and oxidative stress, anti-thrombotics, anti-platelet agents and agents that counteract free hemoglobin/heme. We also discuss gene therapy, which holds promise of a cure, although its widespread application is currently limited by technical challenges and the expense of treatment. We thus propose that developing systems-oriented multi-agent strategies based on SCD pathophysiology is needed to improve to improve the quality of life and survival of people with SCD.

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“…In vitro and in vivo experiments showed that Lapdesf-4c did not exhibit mutagenic and genotoxic effects [9]. Lapdesf-4c also reversed the priapism in sickle transgenic murine models displaying low NO bioavailability after 3-week treatment by inducing phosphodiesterase-5 (PDE-5) expression and reducing protein expression of ROS markers [8,10]. Although such activities suggested a protective profile of Lapdesf-4c in the ED, there is no investigation of those vascular effects.…”

Section: Introductionmentioning

confidence: 99%

Vascular Effects of the Fetal Hemoglobin Inducer Agent 3-(1,3-Dioxoisoindolin-2-yl) Benzyl Nitrate

et al. 2022

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Vascular endothelium is a protective layer of cells lining the lumen of blood vessels that plays important roles by releasing factors responsible for controlling the vascular tone, regulating the expression of pro-inflammatory cytokines, and expressing adhesion molecules involved in vascular hemostasis. Imbalance of vascular properties leads to endothelial dysfunction (ED) and cardiovascular damage. Some diseases, such as sickle cell anemia, are characterized by ED with reduction in the levels of nitric oxide (NO). Previously, we have shown that the fetal hemoglobin inducer agent 3-(1,3-dioxoisoindolin-2-yl) benzyl nitrate (Lapdesf-4c) could act as NO donor, inhibiting platelet aggregation and reducing the inflammation associated with SCA. However, the vascular effect of this compound was not yet studied. Herein, we evaluated the effects of Lapdesf-4c in vascular reactivity experiments using aortic rings from male Wistar rats (300 g/90 days). We have found that Lapdesf-4c induced vasodilation in the presence (E+) or absence of endothelium (E−) with an average of EMax values of 101.8 ± 3.33% and 111.8 ± 3.21%. The mechanism of action was studied using 1H-[1,2,4]oxadiazolo[4,3-alpha]quinoxalin-1-one (ODQ), L-NG-nitroarginine methyl ester (L-NAME), and hydroxocobalamin. The EMax values for those pathways were hydroxocobalamin (30.6 ± 2.21%), ODQ (4.75 ± 0.51%), and L-NAME (109 ± 3.65), suggesting that Lapdesf-4c exhibits NO-dependent mechanisms. Lapdesf-4c was able to prevent angiotensin-induced ED after incubation of aorta rings for 1 h. We found based on the concentration–effect curve using acetylcholine (ACh) that pEC50 values for the control, Ang II, and combination of (Ang II + Lapdesf-4c) were 6.73, 6.46, and 7.15, respectively. In conclusion, Lapdesf-4c has emerged as a new drug candidate that can promote vasodilation and act as a protective agent against ED, being useful to prevent vascular damage.

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A thalidomide–hydroxyurea hybrid increases HbF production in sickle cell mice and reduces the release of proinflammatory cytokines in cultured monocytes

Cited by 11 publications

References 24 publications

Phthalimide as a versatile pharmacophore scaffold: Unlocking its diverse biological activities

Phthalimide as a versatile pharmacophore scaffold: Unlocking its diverse biological activities

Therapeutic strategies for sickle cell disease: towards a multi-agent approach

Vascular Effects of the Fetal Hemoglobin Inducer Agent 3-(1,3-Dioxoisoindolin-2-yl) Benzyl Nitrate

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