Anticancer activity oF the selected dipyridothiazines and

Anticancer activity oF the selected dipyridothiazines and

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Abstract
Seventeen selected newly synthesized azaphenothiazines,
being tricyclic 10-substituted dipyridothiazines A1-A8
and pentacyclic 6-substituted diquinothiazines B1-B9
were investigated in vitro against the cell lines of 9 types
of human cancer: leukemia, melanoma, non-small cell
lung cancer, colon cancer, CNS cancer, ovarian cancer,
renal cancer, prostate cancer and breast cancer in National
Cancer Institute, Bethesda, USA. This study showed that
the cell lines of all 9 cancer types were sensitive to our
compounds. Two dipyridothoazines A and all diquinothiazines B were active against at least one cancer cell line.
Pentacyclic quinothiazines B were much more active than
tricyclic dipyridothiazines A. To our knowledge this study
is a first demonstration of significant anticancer activities
of azaphenothiazines.
Key words: phenothiazines, azaphenothiazines, dipyridothiazines, diquinothiazines, anticancer activity
Introduction
Phenothiazines are significant class of heterocyclic
compounds for their interesting chemical properties and
widely recognized pharmacological activity (neuroleptic,
antihistaminic, antitussive and antiemetic [1]). Recent reports demonstrated promising anticancer [2, 3], antiplasmid [4] and antibacterial activities [5], reversal of multidrug resistance (MDR) [6, 7] and potential treatment in
Alzheimer’s [8], Creutzfeldt-Jakob [9] and AIDS diseases
[10] of typical and newly synthesized phenothiazines. Significant anticancer activity was found not only for typical
neuroleptic phenothiazines but also for new phenothiazine
derivatives [11-13] which were obtained by introduction of
new pharmacophoric groups at the thiazine nitrogen atom
Streszczenie
Siedemnaście wybranych ostatnio otrzymanych azafenotiazyn, będących tricyklicznymi 10-podstawionymi dipirydotiazynami A1-A8 i pentacyklicznymi 6-podstawionymi
dichinotiazynami B1-B9 zostało przebadanych in vitro na
liniach komórkowych 9 typów ludzkiego nowotworu: białaczki, czerniaka, nowotworów płuc, okrężnicy, centralnego układu nerwowego, jajnika, nerki, prostaty i piersi
w National Cancer Institute w Bethesdzie, USA. Badania
wykazały, że linie komórkowe wszystkich 9 typów nowotworów były wrażliwe na nasze związki. Dwie dipirydotiazyny A i wszystkie dichinotiazyny B były aktywne w
stosunku do co najmniej jednej linii komórek nowotworowych. Pentacykliczne dichinotiazyny B były bardziej aktywne niż tricykliczne dipirydotiazyny A. Według naszej wiedzy
przedstawione badania są pierwszym przykładem znaczących aktywności przeciwnowotworowych azafenotiazyn.
Słowa kluczowe: fenotiazyny, azafenotiazyny, dipirydotiazyny, dichinotiazyny, aktywność przeciwnowotworowa
and by substitution of the benzene ring with the naphthalene ring to form benzophenothiazines and dibenzothiazines.
We modified the phenothiazine structure with the pyridine and quinoline rings to form new azaphenotiazines
being 10-substituted dipyridothiazines (10-substituted 2,7diazaphenothiazines) and 6-substituted diquinothiazines
(6-substituted dibenzo-1,9-diazaphenothiazines). Some of
these compounds exhibit very significant anticancer activity determined in National Cancer Institute in Bethesda,
USA. The most active turned out to be 6-chloroethylureidoethyldiquinothiazine with growth inhibition GI50 = 0.04
μg/ml (40 ng/ml) against melanoma line SK-MEL-5 [14].
In this paper, we demonstrate the anticancer activity of less
active dipyridothiazines A1-A8 and diquinothiazines B1-B9
COPYRIGHT‚'RUPADR!2+WIECIÊSKIEGO)33.†
determined against cancer cell lines in order to discuss the
structure-activity relationship and to search for effective anticancer drugs.
Materials and methods
Chemicals
10-Substituted tricyclic dipyrido[3,4-b;3’,4’-e][1,4]thiazines A1-A8 and 6-substituted pentacyclic diquino[3,2b;2’,3’-e][1,4]thiazines B1-B9, depicted in Fig. 1, were
synthesized according to the recently described procedures
[15-18]. These compounds possess the alkyl, aryl, heteroaryl, N,N-dialkylaminoalkyl, N-acylaminoalkyl and N-sulfonylaminoalkyl groups at the thiazine nitrogen atom.
Assay for anticancer activity
The anticancer activity parameter such as the percentage of
growth (PG in %) of azaphenothiazines A1-A8 and B1-B9 was
determined by the dose-response curve using the cell lines of 9
types of human cancers (leukemia, non-small cell lung cancer,
colon cancer, central nervous system cancer, melanoma, ovarian cancer, renal cancer, prostate cancer and breast cancer cell
lines) at concentration of 10-5 M/l in National Cancer Institute
(Bethesda) in Vitro Anticancer Drug Discovery Screen Program [19]. Azaphenothiazines which give lower PG value are
considered as more potent anticancer compounds.
Results and discussion
The anticancer activities of dipyridothiazines A1-A8 and
diquinothiazines B1-B9, as the PG values, were shown in
Tables 1 and 2, respectively. To short this review, the discussion was limited to those compounds which exhibit the
PG values below or around 60% and to 28 cancer cell lines.
As one can see from Tables diquinothiazines B1-B9 turned
out to be more active than dipyridothiazines A1-A8. Below,
R
N
N
A2.
Anti-breast cancer activity
4 Diquinothiazines (B1,B3, B6 and B8) were found active against MCF7 line and 3 diquinothiazines (B1, B8 and
B9) against T-47D line, 2 diquinothiazines (B5 and B7)
against MDA-MB231/ATCC line and diquinothiazines B7
against HS578T line. Dipyridothiazine B1 showed activity
against HS578T line. Compound B1 showed the most potent
activity with the remarkable PG values of 7 % and 14%.
Anti-leukemia activity
Diquinothiazine B3, B4 and B8 exhibit activity against
SR line.
Anti-renal cancer activity
It is worth noting that all diquinothiazines (B1-B9) and 2
dipyridothiazine (A1 and A2) exhibit potent activity against
UO-31 line. The most active was compound B6 with the PG
value of 19%.
Anti-melanoma activity
6 Diquinothiazines (B1, B2, B4-B6 and B8) showed activity against SK-MEL2 line and diquinothiazine B8 against
UACC-62 line.
Anti-colon cancer activity
Diquinothiazines B1 and B8 exhibited activity against
KM12 and HCT-116 lines, respectively.
N
N
R
N
N
S
NO2
N
R
NSC No
743522/1
B1. -CH2CH2CH2CH3
743518/1
B2.
O2N
H3C
H3C
Anti-non-small cell lung cancer activity
Whereas only dipyridothiazine A1 and diquinothiazines
B5 were active against EKVX line, 6 diquinothiazines (B1,
B4, B5, B7-B9) were found active against HOP-92 line.
Some other compounds were only a little less active.
S
R
A1. -CH3
A3.
there is short review of antiproliferative activities against
the cell lines of 9 types human cancers.
CH2
NSC No
744651/1
744654/1
B3
Cl
744652/1
B4..
NO2
744653/1
743523/1
N
A4..
N
N
743524/1
B5.
Cl
O
A5. -CH2CH2CH2 N
743521/1
O
A6. -CH2CH2N(C2H5)2
743519/1
A7. -CH2CH(CH3)CH2N(CH3)2 743525/1
A8. -CH2CH2CH2NHCOCH3
743520/1
744655/1
N
B6. -CH2CH2NHCOCH3
B7. -CH2CH2CH2NHCOCH3
B8. -CH2CH2CH2NHCOOC2H5
B9. -CH2CH2CH2NHSO2C6H4CH3
744657/1
744661/1
744663/1
744662/1
Fig. 1. Structures of dipyridothiazines A1-A8 and diquinothiazines B1-B9 with
National Cancer Institute
code numbers
&ARM0RZEGL.AUK
Tab. I. Anticancer activity (PG in % at concentration of 10-5 M) of dipyridothiazines A1-A8
Non-small cell
Compd’s lung cancer
number
HOP-92 NCI-H522
EKVX
HS578T
A1
A2
A3
A4
A5
A6
A7
A8
49
89
79
>90
>90
>90
>90
>90
64
>90
>90
>90
>90
>90
>90
>90
85
80
77
90
>90
89
87
90
>90
88
73
>90
>90
90
90
78
Renal cancer
Compd’s
number RXF-393
A1
A2
A3
A4
A5
A6
A7
A8
>90
84
>90
>90
>90
>90
>90
>90
Melanoma
Compd’s
number UACC-62
A1
A2
A3
A4
A5
A6
A7
A8
>90
>90
81
>90
>90
>90
87
>90
Breast cancer
Leukemia
MDA-MB231-ATCC
90
77
85
>90
>90
>90
>90
85
K-562
RPMI-822
>90
87
83
>90
89
>90
>90
>90
>90
>90
86
>90
>90
>90
88
>90
Ovarian cancer
CNS Cancer
UO-31
ACHN
OVCAR-8
SNB-75
SF-295
40
56
>90
-
>90
>90
75
>90
>90
>90
>90
>90
>90
87
83
90
>90
>90
>90
>90
85
>90
>90
90
87
89
>90
83
>90
>90
87
>90
>90
88
>90
>90
Prostate cancer
Colon cancer
U251
PC-3
COLO 205
>90
>90
88
>90
>90
>90
>90
>90
>90
88
>90
>90
>90
>90
>90
>90
>90
>90
90
>90
>90
>90
>90
>90
Anti-ovarian cancer activity
Diquinothiazine B7 showed
activity against SK-OV-3 line.
Anti-CNS cancer activity
Diquinothiazine B7 was
found to be active against U251
and SNB-75 lines.
Anti-prostate cancer activity
Diquinothiazine B8 showed
activity against PC-3 line.
This short commentary
demonstrates anticancer potential and selectivity of our
new azaphenothiazines. Some
compounds exhibited significant antiproliferative activity,
for example compounds B1,
B6, B5, B8 and B7 against
the selected cell lines (Table
2). It worth noting that less
active dipyridothoazines A
showed antiproliferative activity against to the selected cancer lines with the PG values
of 40-90% (Table 1). Taking
into account the phenothiazine
structures A and B, it seems
that the multicyclic ring system is much more biological
potent than the nature of the
pharmacophoric substituents.
Tab. II. Anticancer activity (PG in % at concentration of 10-5 M) of diquinothiazines B1-B9
Compd’s
number
B1
B2
B3
B4
B5
B6
B7
B8
B9
Compd’s
number
B1
B2
B3
B4
B5
B6
B7
B8
B9
Non-small cell
lung cancer
HOP-92
HOP-62
28
>90
73
84
90
62
80
39
>90
75
89
47
69
49
76
69
>90
R e n a l
Melanoma
cancer
Breast cancer
EKVX
MCF7
HS578T
85
>90
>90
>90
69
86
86
74
72
7
61
37
>90
74
53
60
45
70
>90
89
88
85
83
>90
63
82
>90
Leukemia
MDA-MB231/
ATCC
76
>90
>90
84
68
80
66
77
83
T-47D
SR
14
>90
77
89
83
80
83
39
64
77
81
65
54
78
87
80
44
83
Colon cancer
Ovarian cancer
CNS cancer
Prostate
cancer
UO-31
SK-MEL2
UACC-62
KM12
HCT-116
SK-OV-3
SNB-75
U251
PC-3
22
39
43
37
27
19
29
24
32
62
67
78
64
39
63
76
62
71
>90
85
85
77
78
>90
78
59
76
68
>90
>90
>90
>90
>90
82
-
>90
>90
85
90
>90
>90
87
68
>90
>90
>90
>90
>90
>90
>90
65
88
>90
>90
>90
>90
>90
>90
>90
60
>90
>90
>90
>90
>90
>90
86
>90
57
>90
>90
79
>90
81
73
86
75
67
82
COPYRIGHT‚'RUPADR!2+WIECIÊSKIEGO)33.†
Conclusions
This study showed that the cell lines of all 9 cancer types
were sensitive to our compounds. Two dipyridothoazines
A and all diquinothiazines B were active against at least
one cancer cell line. Pentacyclic quinothiazines B were
much more active than tricyclic dipyridothiazines A. To our
knowledge this study is a first demonstration of significant
anticancer activities of azaphenothiazines.
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Address for correspondence:
dr hab. Krystian Pluta
The Medical University of Silesia
Department of Organic Chemistry
Jagiellońska 4, 41-200 Sosnowiec, Poland
e-mail: [email protected].