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Synthesis and characterization of new

thiosemicarbazone conjugates and their Copper (II)


complexes with potential antiproliferative activity
Author – Iuliana BEȘLEAGA, BSc
The State University ”DIMITRIE CANTEMIR” (Republic of Moldova),
Faculty of Fundamental Sciences, The Department of Chemistry, Mathematics and Informatics

Supervisor – Ao. Uni.- Prof. Dr. Vladimir B. ARION

Vienna - 2019
1. Designing new series of thiosemicarbazone conjugates -
thiosemicarbazones (HL1-HL3) as a triapine analogs.
Objectives 2. Obtaining and characterization of coordinative compounds
of the new thiosemicarbazone conjugates with cooper (II)

NH2
S

N NH2
OH OH
N N NH2
S H S
Triapine
N N
N N N N N N
H H H H
OH
(HL )1
S (HL3)

N
N N N
H H

(HL2)
2
General scheme of synthesis of the ligands HL – HL 1 3

OH R OH
R
S S

+
H2N N
O
N N N N N
N H H H H

R1
R1 HL1: R=H, R1= H
HL2: R=H, R1= CH3
HL3: R=NH2, R1= H

3
Synthesis of HL1
2-formylpyridine N4-(4-hydroxy-3,5-dimethylphenyl) thiosemicarbazone

H H
N N OH
+ H2N S
O
N N
S
N N N
OH H H

2-formylpyridine N-(4-hydroxy-3,5-dimethylphenyl)hydrazinecarbothioamide 2-formylpyridine


4
N -(4-hydroxy- 3,5-dimethylphenyl) thiosemicarbazone

Reaction conditions:
• Solvent – ethanol
• Stirring at 85 ⁰C for 2 hours
• Yield: 85.41 % 4
Characterization of HL1
2-formylpyridine N4-(4-hydroxy-3,5-
dimethylphenyl) thiosemicarbazone

OH

OH
S

N
N N
H
HN
H
S N
N
N N
H

E isomer Z isomer 5
Synthesis of HL2
2-acetylpyridine N4-(4-hydroxy-3,5-dimethylphenyl) thiosemicarbazone
H H
N N OH
+ H2N S
O
N S N
OH N N N
H H

2-acetylpyridine 2-acetylpyridine
N-(4-hydroxy-3,5-dimethylphenyl)hydrazinecarbothioamide 4
N -(4-hydroxy-3,5-dimethylphenyl)thiosemicarbazone

Reaction conditions:
• Solvent – ethanol
• Stirring at 85 ⁰C overnight
• Yield: 67.04 % 6
Characterization of HL2
2-acetylpyridine N4-(4-hydroxy-3,5-
dimethylphenyl) thiosemicarbazone

OH

OH
S

N
N N
H
HN
H
S N
N
N N
H

E isomer Z isomer 7
O O

N Br

NH (*) 1. Obtaining of N-
Synthesis of HL3 (**) NH2
(boc)protected 3-amino-2-
pyridinecarboxaldehyde
3-amino-2-formylpyridine N Br
3-amino-2-bromopyridin
N4-(4-hydroxy-3,5- tert-butyl-(2-bromopyridin-3-yl)carbamate
H
dimethylphenyl) O O
H H
N O

thiosemicarbazone
N N
H2N O
NH
HCl N
+ S
OH
O N
N NH

2. Schiff base NH2 OH


HN S

condensation reaction S

with N
N
N N
hydrazinecarbothioamide H H

3-amino-2-formylpyridine
precursor 4
N -(4-hydroxy-3,5-dimethylphenyl)thiosemicarbazone
HO

*Kowol C.R., Trondl R., Heffeter .P, Arion V.B., Jakupec M.A., Roller A., Galanski M., Berger W., Keppler B.K. Impact of metal coordination on cytotoxicity of 3-aminopyridine-2-
carboxaldehyde thiosemicarbazone (triapine) and novel insights into terminal dimethylation. J. Med. Chem. . 2009, 52(16):5032-43

**Venuti M.C., Stephenson A.R, Alvarez R., Bruno J.J., Strosberg A.M. Inhibitors of cyclic AMP phosphodiesterase. 3. Synthesis and biological evaluation of pyrido and imidazolyl
8 analogs of
1,2,3,5-tetrahydro-2-oxoimidazo[2,1-b]quinazoline. J. Med. Chem.1988. 1988, 31, 11, 2136-2145.
Synthesis of HL3
2. Schiff base condensation reaction with hydrazinecarbothioamide fragment
• Solvent – ethanol: water (3:1)
• Stirring at the room temperature for 1 hour and then the temperature was
increased until 85 ⁰C, that was mentioned for 7 hours.
• Yield: 87.93 %
OH
OH
S

N
N N
H
NH2 HN H2N H
N
S
N
N N
H
E isomer Z isomer

9
Characterization of HL3
3-amino-2-formylpyridine N4-(4-hydroxy-3,5-dimethylphenyl) thiosemicarbazone

10
Synthesis of
Copper (II) complexes Cl
OH OH
N S N Cu S
CuCl2·2 H2O + Cl
N N
N N N N
H H H H
R R1 R R1
1
HL : R=H, R1= H Cu(HL1)Cl2: R=H, R1= H
HL2: R=H, R1= CH3 2
Cu(L )Cl: R=H, R1= CH3
HL3: R=NH2, R1= H Cu(HL3)Cl2: R=NH2, R1= H

Reactions conditions:
• Inert conditions
• Solvent - degassed methanol
• Room temperature 11
Characterization of Cu(HL )Cl 2
1

12
Stability of Cu(HL )Cl 2 1
H

OH O O
S S S

N N N
N N N N N N N N N
H H H H H

Cu(HL1)Cl2
CM = 53,2092 · 10-6 mol/L
1.1

0.9

0.7

0.5

0.3

0.1

-0.1
240 290 340 390 440 490 540 590 640 690

13
Characterization of Cu(L )Cl
2

14
Characterization of Cu(HL )Cl 2
3

15
Stability of Cu(HL )Cl 2 3
H

NH2 NH2 O
NH2 OH O
S S
S

N N
N
N N N N N N
N N N H
H H H H

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• Incubation time: 72 h
• Cell number: 10 000 cells/well
MTT results • Human cancer cell lines: Colo-205 and Colo-320
• Human non-cancer lung MRC-5 cell line
• Reference compound: doxorubicin

*
Selectivity factors (SFs) for Colo-205 and Colo-320 cancer cell lines over non-cancerous MRC-5 cells.
SF(205) = IC50 MRC-5/IC50 Colo-205 17
SF(320) = IC50 MRC-5/IC50 Colo-320
Thank you for
attention
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