8-Alkylmercaptocaffeine derivatives: antioxidant, molecular docking, and in-vitro cytotoxicity studies.

Published on Apr 9, 2021in Bioorganic Chemistry4.831
· DOI :10.1016/J.BIOORG.2021.104900
Saman Sargazi4
Estimated H-index: 4
,
Sheida Shahraki1
Estimated H-index: 1
+ 5 AuthorsRamin Saravani10
Estimated H-index: 10
Source
Abstract
Abstract Due to their unique pharmacological characteristics, methylxanthines are known as therapeutic agents in a fascinating range of medicinal scopes. In this report, we aimed to examine some biological effects of previously synthesized 8-alkylmercaptocaffeine derivatives. Cytotoxic and antioxidative activity of 8-alkylmercaptocaffeine derivatives were measured in malignant A549, MCF7, and C152 cell lines. Assessment of cGMP levels and caspase-3 activity were carried out using a colorimetric competitive ELISA kit. Computational approaches were employed to discover the inhibitory mechanism of synthesized compounds. Among the twelve synthesized derivatives, three compounds (C1, C5, and C7) bearing propyl, heptyl, and 3-methyl-butyl moieties showed higher and more desirable cytotoxic activity against all the studied cell lines (IC50   0.05) and exhibited no marked ameliorating effects on oxidative damage (P > 0.05). Computational studies showed that H-bond formation between the nitrogen atom in pyrazolo[4,3-D] pyrimidine moiety with Gln817 and creating a hydrophobic cavity result in the stability of the alkyl group in the PDE5A active site. We found that synthesized 8-alkylmercaptocaffeine derivatives induced cell death in different cancer cells through the cGMP pathway. These findings will help us to get a deeper insight into the role of methylxanthines as useful alternatives to conventional cancer therapeutics.
References64
Newest
#1Yang Gao (Stanford University)H-Index: 4
#2Gözde Eskici (Stanford University)H-Index: 2
Last. Richard A. Cerione (Cornell University)H-Index: 13
view all 8 authors...
Heterotrimeric G proteins communicate signals from activated G protein-coupled receptors to downstream effector proteins. In the phototransduction pathway responsible for vertebrate vision, the G protein-effector complex is composed of the GTP-bound transducin α subunit (GαT·GTP) and the cyclic GMP (cGMP) phosphodiesterase 6 (PDE6), which stimulates cGMP hydrolysis, leading to hyperpolarization of the photoreceptor cell. Here we report a cryo-electron microscopy (cryoEM) structure of PDE6 comple...
4 CitationsSource
#1Gary A. Piazza (USA: University of South Alabama)H-Index: 39
#2Antonio Ward (USA: University of South Alabama)H-Index: 2
Last. Gang ZhouH-Index: 17
view all 10 authors...
Although numerous reports conclude that nonsteroidal anti-inflammatory drugs (NSAIDs) have anticancer activity, this common drug class is not recommended for long-term use because of potentially fatal toxicities from cyclooxygenase (COX) inhibition. Studies suggest the mechanism responsible for the anticancer activity of the NSAID sulindac is unrelated to COX inhibition but instead involves an off-target, phosphodiesterase (PDE). Thus, it might be feasible develop safer and more efficacious drug...
3 CitationsSource
#1Julie Birkmose Axelsen (Aarhus University Hospital)H-Index: 4
#2Stine Andersen (Aarhus University Hospital)H-Index: 9
Last. Asger Andersen (Aarhus University Hospital)H-Index: 13
view all 11 authors...
Background Several antineoplastic drugs have been proposed as new compounds for pulmonary arterial hypertension treatment but many have cardiotoxic side effects. The chemotherapeutic agent 6-mercaptopurine may have an effect in treatment of pulmonary arterial hypertension but at the same time, its effects on the afterload adaption of the right ventricle is unpredictable due to interaction with multiple downstream signalling pathways in the cardiomyocytes. We investigated the direct cardiac effec...
5 CitationsSource
#1Stefania Catalano (University of Calabria)H-Index: 41
#2Salvatore Panza (University of Calabria)H-Index: 18
Last. Ines BaroneH-Index: 29
view all 12 authors...
The overexpression of phosphodiesterase (PDE) 5 is frequently found in various human cancers, such as those of the breast. However, PDE5’s role in the tumor microenvironment is still unknown. As PDE5 represents a high-value therapeutic target, we investigated whether the expression and function of PDE5 in breast cancer-associated fibroblasts (CAFs) may be clinically relevant to malignant progression. PDE5 expression was increased in human breast cancer stroma compared with normal stroma and was ...
8 CitationsSource
#2Ramin SaravaniH-Index: 10
Last. Ali Shahraki (University of Sistan and Baluchestan)H-Index: 4
view all 3 authors...
Background: This study aimed to investigate Levisticum officinale hydroalcoholic extract (LOHE) effect on both cGMP signaling pathway and phosphodiesterase 5 (PDE5) gene expression pattern and to examine the role of LOHE in apoptosis induction of MCF-7 and MDA-MB-468 cell lines. Methods: The half maximal inhibitory concentration (IC50) of LOHE was examined in both cell lines using the MTT assay. Using IC50 values of LOHE on both cells, the type of cell death was detected by flowcytometric analys...
3 CitationsSource
#1Inés Mármol (University of Zaragoza)H-Index: 10
#2Javier Quero (University of Zaragoza)H-Index: 7
Last. Elena Cerrada (University of Zaragoza)H-Index: 23
view all 4 authors...
Due to the increasing incidence and high mortality associated with colorectal cancer (CRC), novel therapeutic strategies are urgently needed. Classic chemotherapy against CRC is based on oxaliplatin and other cisplatin analogues; however, platinum-based therapy lacks selectivity to cancer cells and leads to deleterious side effects. In addition, tumor resistance to oxaliplatin is related to chemotherapy failure. Gold(I) derivatives are a promising alternative to platinum complexes, since instead...
17 CitationsSource
#1Yinuo Wu (SYSU: Sun Yat-sen University)H-Index: 14
#2Qian Zhou (SYSU: Sun Yat-sen University)H-Index: 4
Last. Hai-Bin Luo (SYSU: Sun Yat-sen University)H-Index: 22
view all 14 authors...
To identify phosphodiesterase-9 (PDE9) as a novel target for the treatment of vascular dementia (VaD), a series of pyrazolopyrimidinone analogues were discovered based on a hit 1. Hit-to-lead optimization resulted in a potent inhibitor 2 with excellent selectivity and physicochemical properties to enable in vivo studies. Oral administration of 2 (5.0 mg/kg) caused notable therapeutic effects in the VaD mouse model, providing a promising lead or chemical probe for investigating the biological fun...
5 CitationsSource
#1Wei Yang (Monash University, Clayton campus)H-Index: 3
#2Blake T. Riley (Monash University, Clayton campus)H-Index: 6
Last. Sheena McGowan (Monash University, Clayton campus)H-Index: 25
view all 7 authors...
The M1 and M17 aminopeptidases are metallo-exopeptidases that rely on the presence of divalent cations, usually zinc, in their active site for proteolytic activity. They are from separate protease superfamilies, however, members often have overlapping substrate specificity. Inhibitors of one or both enzymes can be used to modulate hypertension, reduce proliferation of certain types of cancers and control malaria parasites. Current inhibitors act to chelate the zinc ions in the active site, locki...
9 CitationsSource
#1Yuichiro Oda (Kyushu University of Health and Welfare)H-Index: 1
#2Muneaki Hidaka (Kyushu University of Health and Welfare)H-Index: 6
Last. Akito Suzuki (Kyushu University of Health and Welfare)H-Index: 3
view all 3 authors...
Cisplatin is an anticancer agent and induces DNA interstrand cross-links (ICLs). ICLs activate various signaling processes and induce DNA repair pathways, including the Fanconi anemia (FA) pathway. FA complementation group D2 (FANCD2) is monoubiquitinated in response to DNA damage, leading to activation of the DNA double-strand-break repair protein, RAD51. Caffeine increases the anticancer activity of cisplatin by inhibiting DNA repair; however, details of the mechanism remain unclear. We invest...
3 CitationsSource
#1Hanyang Liu (Nanjing Medical University)H-Index: 5
#2Yan Zhou (Nanjing Medical University)H-Index: 3
Last. Liming Tang (Nanjing Medical University)H-Index: 4
view all 3 authors...
: Caffeine is one of the most widely consumed substances found in beverages, and has demonstrated anticancer effects in several types of cancer. The present study aimed to examine the anticancer effects of caffeine on gastric cancer (GC) cells (MGC‑803 and SGC‑7901) in vitro, and to determine whether the apoptosis‑related caspase‑9/-3 pathway is associated with these effects. The sustained antiproliferative effects of caffeine on gastric cancer were also investigated. GC cell viability and proli...
23 CitationsSource
Cited By0
Newest