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Synthesis and biological evaluation of novel bile acid-nucleoside conjugates
published results and work in progress
Maria Luisa NAVACCHIA
CNR ISOF
CNR-ISOF
Massimo Capobianco
Maria Luisa Navacchia
UNIFE-Dipartimento di Scienze Chimiche e Farmaceutiche
Daniela Perrone
Elena Marchesi
Lara Mari
UNIFE-Dipartimento di Scienze Chimiche Mediche
Riccardo Gavioli
Fabio Sforza
biological evaluation
•synthesis and characterization of
modified bile acids
• click-chemistry
synthesis and characterization
of modified nucleosides
Conjugate synthesis via click-chemistry
i: CuSO4 . 5 H2O, sodium ascorbate, THF–tBuOH–H2O (1.5 : 1 :1), 25 °C, 18 h, 70%; or microwave 80 °C, 30 min, 73%.
Synthesis of 8-alkynylated-2’-deoxyadenosines
This reaction can be smoothly performed in water and leads to a simple purification of the thioalkylnylated
nucleoside that only requires the extraction of the compound with warm EtOAc from the aqueous crude mixture.
M. L. Capobianco and M. L. Navacchia PCT Int. Appl. WO 2012164484 A1 2012
This reaction can be smoothly performed and leads to a simple purification of the alkylnylated
nucleoside that requires a filtration on florisil.
n
N
NN
N
NH2
O
OH
OH
BrN
NN
N
NH2
O
OH
OH
n
DMF
Pd(PPh3)2Cl2CuI
50 °C
+
n = 3
SH
N
NN
N
NH2
O
OH
OH
BrN
NN
N
NH2
O
OH
OH
S
+H2O, TEA
100 °C, 2 h3
3
Biological evaluation
in vitro cytotoxicity toward human fibroblast cells and anti-proliferative activity against four human
cancer cell lines: Leukemic T Jurkat and K562, colon carcinoma HCT116 and ovarian cancer A2780
Cytotoxic activity of bile acid-based conjugates and
alkynyl deoxyadenosines dA-A, HdA-A, and SdA-A on human cancer cell lines and human fibroblast cellsa
Percentage of apoptotic K562 cells determined after 24 h treatment with HdA-CDC, SdA-CDC and HM-CDC (50–10 mM) by annexin V staining.
Conclusion
• Best activity was shown by CDC- based derivatives and could be correlated to the lipophilicity and to the 7a-OH group orientation;
• furthermore, except dA-UDC and HM-bile acid series, all new conjugates did not show any significant cytotoxicity towards the human fibroblast cells whereas some of them strongly and selectively inhibited cell proliferation and induced apoptosis in leukemic K562 cells; • therefore, these derivatives constitute a starting lot of candidate drugs.
O
OMe
OH
X
…however many questions are still open
Do other nucleobases work?
Does the ribo form work?
How much important is the triazole ring?
N
NN
N
NH2
O
OHOH
OH
n
NH
NN
N
O
O
H (OH)OH
OHNH
2
n
NH
N
O
O
H (OH)OH
OHO
n
H-A-A H-dG-A, H-G-A
n = 3 n = 3
n = 3
H-dU-A, H-U-A
click
O
OMe
N3
OHN
3
OH
OH
O
NH
N3
OH
SO3
N3-TUDCA
2
Nor-23-N3-CDC 7aOH
Nor-23-N3-UDC7-OH
N3-CDC 7aOH
N3-UDC7-OH
A new lot of 27 bioconjugates is waiting for the biological assay
SH
OH
OH
N
NN
N
NH2
O
OH
OH
S
OH
OH
N
NN
N
NH2
O
OH
OH
Br
+
H2O, TEA
100 °C, 2h
Nor-23-SH-CDC 7aOH
Nor-23-SH-UDC7-OH
Adenosine Or Deoxyadenosine Derivatives Modified At Position 8 And A Method Of Synthesis Thereof ; Massimo L. Capobianco and Maria Luisa Navacchia PCT Int. Appl. WO 2012164484 A1 2012. Labeling Deoxyadenosine for the Preparation of Functional Conjugated Oligonucleotides; Massimo L. Capobianco,* Elena Marchesi, Daniela Perrone and Maria Luisa Navacchia Bioconj., 2013, 24, 1398-1407. Synthesis and in vitro cytotoxicity of deoxyadenosine-bile acid conjugates linked with 1,2,3-triazole; Daniela Perrone,* Olga Bortolini, Marco Fogagnolo, Elena Marchersi, Lara Mari, Chiara Massarenti, Maria Luisa Navacchia,* Fabio Sforza, Katia Varani and Massimo Luigi Capobianco New J. Chem., 2013, 37, 3557-3557.
References