Synthesis and biological activity of ester derivatives of mycophenolic acid and acridines/acridones as potential immunosuppressive agents

Cholewiński, Grzegorz; Iwaszkiewicz-Grześ, Dorota; Trzonkowski, Piotr; Dzierzbicka, Krystyna

doi:10.3109/14756366.2015.1077821

Cited by 16 publications

(10 citation statements)

References 43 publications

(55 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The MPA possesses electrophilic centre at the acyl carbon in the lactone ring and free phenol group. Protection of the phenolic –OH using Ac 2 O (mycophenolic acid acetate), tert -butyldimethylsilyl triflate or tert -butyldimethylsilyl chloride (7-O-TBDMS-mycophenolic acid) and selective hydrolysis of the same has been reported and used for amide formation 21 . Protection and deprotection approach increases the number of steps leading to lower overall yield.…”

Section: Resultsmentioning

confidence: 99%

“…The MPA and its related forms MMF or MPA sodium ( 3 ) (MPS) cause dose-limiting gastrointestinal (GI) toxicity. However, adverse effects related to the treatment with MPA-based drugs, such as diarrhoea, leukopenia, sepsis and vomiting, are the barriers to the administration of higher doses and more effective treatment 21 . The competitive IMPDH inhibitors such as tiazofurin ( 4 ), ribavirin ( 5 ) and mizoribine ( 6 ) (after intracellular activation by phosphorylation) are nucleoside analogues and derivatives thereof 22 have unfavourable tolerability profiles too.…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, antitumour activities of several derivatives of 1 are reported 27 , 28 . The MPA conjugates possessing amide and ester linkages ( 7–12 , Figure 2 ) exhibited potent anticancer properties 21 , 29–31 . These findings strongly support the role of 1 as a potential anticancer drug.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Newer human inosine 5′-monophosphate dehydrogenase 2 (hIMPDH2) inhibitors as potential anticancer agents

Shah

Kharkar

2018

Journal of Enzyme Inhibition and Medicinal Chemistry

View full text Add to dashboard Cite

Human inosine 5′-monophosphate dehydrogenase 2 (hIMPDH2), being an age-old target, has attracted attention recently for anticancer drug development. Mycophenolic acid (MPA), a well-known immunosuppressant drug, was used a lead structure to design and develop modestly potent and selective analogues. The steep structure–activity relationship (SAR) requirements of the lead molecule left little scope to synthesise newer analogues. Here, newer MPA amides were designed, synthesised and evaluated for hIMPDH2 inhibition and cellular efficacy in breast, prostate and glioblastoma cell lines. Few title compounds exhibited cellular activity profile better than MPA itself. The observed differences in the overall biological profile could be attributed to improved structural and physicochemical properties of the analogues over MPA. This is the first report of the activity of MPA derivatives in glioblastoma, the most aggressive brain cancer.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Newer human inosine 5′-monophosphate dehydrogenase 2 (hIMPDH2) inhibitors as potential anticancer agents

Shah

Kharkar

2018

Journal of Enzyme Inhibition and Medicinal Chemistry

View full text Add to dashboard Cite

show abstract

“…The final mycophenolic acid was identical with purchased one (Tocris Bioscience), and we were able to use it in synthesis of the novel analogues of MPA. [34][35][36][37] 1.…”

Section: Resultsmentioning

confidence: 99%

Modifications of total synthesis of mycophenolic acid

Cholewiński¹,

Ugarte²,

Siebert³

et al. 2018

10.5267/j.ccl

Self Cite

View full text Add to dashboard Cite

show abstract

“…Nevertheless, efforts to produce new anticancer acridine derivatives are ongoing (Tang et al 2012 ; Othman and Kozurkova 2018 ). One way of constructing new derivatives is by binding acridine compounds with other biologically active elements, e.g., muramyl dipeptide (MDP), tuftsin, peptide nucleic acids (PNA), or antiinflammatory drugs such as ibuprofen, ( S )-naproxen, acetylsalicylic acid (Gensicka-Kowalewska et al 2017 ; Kukowska 2017 ), and mycophenolic acid (MPA) (Cholewinski et al 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Novel therapeutic compound acridine–retrotuftsin action on biological forms of melanoma and neuroblastoma

Cichorek

Ronowska

Gensicka-Kowalewska

et al. 2018

J Cancer Res Clin Oncol

Self Cite

View full text Add to dashboard Cite

PurposeAs a continuation of our search for anticancer agents, we have synthesized a new acridine-retrotuftsin analog HClx9-[Arg(NO2)-Pro-Lys-Thr-OCH3]-1-nitroacridine (named ART) and have evaluated its activity against melanoma and neuroblastoma lines. Both tumors develop from cells (melanocytes, neurons) of neuroectodermal origin, and both are tumors with high heterogeneity and unsatisfactory susceptibility to chemotherapies. Thus, we analyzed the action of ART on pairs of biological forms of melanoma (amelanotic and melanotic) and neuroblastoma (dopaminergic and cholinergic) with regard to proliferation, mechanism of cell death, and effect on the activity of tricarboxylic acid cycle (TAC) enzymes.MethodsThe cytotoxicity of ART was evaluated by XTT and trypan blue tests. Cell death was estimated by plasma membrane structure changes (phosphatidylserine and calreticulin externalization), caspase activation, presence of ROS (reactive oxygen species), activity of tricarboxylic acid cycle enzymes (pyruvate dehydrogenase complex, aconitase, and isocitrate dehydrogenase), NAD level, and ATP level.ResultsART influences the biological forms of melanoma and neuroblastoma in different ways. Amelanotic (Ab) melanoma (with the inhibited melanogenesis, higher malignancy) and SHSY5Y neuroblastoma (with cholinergic DC cells) were especially sensitive to ART action. The Ab melanoma cells died through apoptosis, while, with SH-SY5Y-DC neuroblastoma, the number of cells decreased but not as a result of apoptosis. With Ab melanoma and SH-SY5Y-DC cells, a diminished activity of TAC enzymes was noticed, along with ATP/NAD depletion.ConclusionOur data show that the biological forms of certain tumors responded in different ways to the action of ART. As a combination of retrotuftsin and acridine, the compound can be an inducer of apoptotic cell death of melanoma, especially the amelanotic form. Although the mechanism of the interrelationships between energy metabolism and cell death is not fully understood, interference of ART with TAC enzymes could encourage the further investigation of its anticancer action.Electronic supplementary materialThe online version of this article (10.1007/s00432-018-2776-4) contains supplementary material, which is available to authorized users.

show abstract

Synthesis and biological activity of ester derivatives of mycophenolic acid and acridines/acridones as potential immunosuppressive agents

Cited by 16 publications

References 43 publications

Newer human inosine 5′-monophosphate dehydrogenase 2 (hIMPDH2) inhibitors as potential anticancer agents

Newer human inosine 5′-monophosphate dehydrogenase 2 (hIMPDH2) inhibitors as potential anticancer agents

Modifications of total synthesis of mycophenolic acid

Novel therapeutic compound acridine–retrotuftsin action on biological forms of melanoma and neuroblastoma

Contact Info

Product

Resources

About