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Synopsis
SYNOPSIS
The thesis entitled, “Design, Synthesis and Anticancer Evaluation of
DNA
Interactive
Pyrrolo[2,1-c][1,4]benzodiazepine
Hybrids,
Chrysin
Conjugates and Preparation of some Bioactive Heterocycles” has been divided
into four chapters. Chapter I gives the general introduction about cancer
chemotherapy,
covalent,
and
non-covalent
interactions
of
drug-DNA,
particularly of pyrrolo[2,1-c][1,4]benzodiazepine (PBD) antitumour antibiotics,
flavone derivatives, the use of NaI/AcOH in organic synthesis and the objectives
of the present work. Chapter II comprises of three sections; section A consists of
the design, synthesis and DNA binding affinity of novel chrysin-pyrrolo[2,1c][1,4]benzodiazepine hybrids and their activity. While section B consists of the
design, synthesis and DNA binding affinity of novel quinazolinone-PBD hybrids
and their activity on nine human tumour cell lines. The section C deals with the
design synthesis and DNA binding affinity of novel indolindione-PBD hybrids.
Chapter III comprises of the design, synthesis and in vitro anticancer activity of
novel chrysin conjugates on sixty human tumour cell lines. Chapter IV describes
the application of sodium iodide-acetic acid reagent system for the synthesis of
various bioactive heterocycles through azidoreductive cyclocondensation
process.
Chapter I: General Introduction
Cancer is a disease caused by the malfunctioning of normal cells.
Chemotherapy or the use of chemical agents to destroy the cancer cells is a
mainstay in the treatment of malignancies. A major advantage of chemotherapy
is its ability to treat widespread or metastatic cancer, whereas surgery and
radiation therapies are limited to treating the cancers that are confined to specific
area. The major categories of chemotherapeutic agents are antitumour
antibiotics, topoisomerase I and II inhibitors, DNA interactive agents and other
miscellaneous compounds. The first PBD antitumour antibiotic anthramycin has
I
Synopsis
been described by Leimgruber et. al., about 38 years back, and since then a
number of compounds have been developed on PBDs leading to DNA binding
ligands. Pyrrolo[2,1-c][1,4]benzodiazepines have the potential as regulators of
gene expression with possible therapeutic application in the treatment of genetic
disorders, including cancer.
The pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) are well known class of
antitumour antibiotics with sequence selective DNA binding ability that are
derived from various Streptomyces species. Their mode of interaction with DNA
has been extensively studied and it is considered unique as they bind within the
minor groove of B form DNA. These compounds exert their biological activity by
covalently binding to the C2-amino group of guanine residue in the minor
groove of DNA through the imine or imine equivalent functionality at N10-C11
of PBD moiety.
Figure-1
H3C 8
7
OH H
9 N
6
OCH3
N
HO
11H
10
1
11a
2
N
5
4
3
O
N
H3CO
CONH2
O
DC-81
Anthramycin
N
H
H
O
N
N
O
N
OCH3 H3CO
O
H
O
DSB-120
Cl
O
N
O
N
N
H3CO
O
OH
CBI-PBD Conjugate
II
H
Synopsis
Figure-2
O
O
N
HN
H2N
N
H
N
N
HN
H
N
HH N
N
H
N
DNA
N
DNA
N
N
O
O
11R/S aminal
N10-C11 Imine
PBD-DNA interaction
Certain plant species containing flavonoids have been widely used in
traditional eastern medicine to treat cancer. Actually, some flavonoids such as
baicalain and its glycosides have been clinically used in China for many years.
However, Western medicine has not yet used flavonoids therapeutically.
Attempts are under way to produce new flavonoid derivatives with less toxic
effects.
Figure-3
O
O
O
OH
O
Flavones
O
OH
O
Flavonols
Flavanonol
Chrysin, a flavonoid derivative is generally non toxic; it can be used in
combination with toxic drugs that nowadays are used in cancer therapy in order
to reduce their toxic effects. Although certain studies show that chrysin possesses
synergic effect with other drugs, it was found that it can be used in combination
with topoisomerase poisons or intercalators in order to improve their anticancer
properties.
III
Synopsis
Figure-4
I
MeO
O
O
I
I
AcO
I
O
F3C
O
O
OMe O
CF3
O
OH
MeO
OMe O
OMe O
AcO
CF3
MeO
HO
O
I
OH O
OH O
Chrysin Derivatives
Recent developments in organic synthetic methodologies have witnessed
the emergence of a diverse number of iodine compounds, which have been
utilized successfully in achieving a multitude of chemical transformations in
high yields. Sodium iodide-acetic acid reagent system has been widely employed
towards the synthesis of various bioactive heterocycles.
Chapter II-Section A: Design, synthesis, DNA binding affinity and in vitro
cytotoxicity of novel chrysin-pyrrolo[2,1-c][1,4]benzodiazepine hybrids
Recently, there has been growing interest in modifying and extending the
recognition patterns of DNA binding ligands. Pyrrolo[2,1-c][1,4]benzodiazepine
antitumour antibiotics bind covalently to the N2 of guanine in the minor groove
of DNA. In the past few years several PBD analogues have been designed and
synthesized with the aim of finding related compounds showing better
antitumour activity. The PBDs have been used as novel scaffolds to attach EDTA,
epoxide, (+)-cyclopropapyrroloindole and cyclopropylbenzindole moieties
leading to novel unsymmetrical hybrids of PBD, which have exhibited novel
sequence selective DNA cleaving and cross-linking properties. Chrysin on the
IV
Synopsis
other hand represent an important class of compounds that interact with DNA
either by DNA intercalation or topoisomerase inhibition.
The objective of the present work is to combine the features of both DNA
intercalating and DNA covalent binding properties in the same molecule.
Therefore in this design, chrysin has been linked to the PBD through its C8
position. In this section the synthesis, DNA binding affinity and in vitro
cytotoxicity of these new chrysin-PBD hybrids have been described.
The
precursor
2S-N-[(n-bromoalkyloxy)-5-methoxy-2-nitrobenzoyl]-
pyrrolidine-2-carboxaldehyde diethyl thioacetal 7a-c has been prepared by
employing commercially available vanillin. Oxidation of vanillin followed by
esterification by literature method provides vanillin methyl ester 3. This on
coupling with various n-bromoalkanes gives 4a-c which upon nitration followed
by
ester
hydrolysis
affords
6a-c.
(2S)-Pyrrolidine-2-carboxaldehyde
diethylthioacetal has been coupled to 6a-c to produce the nitrothioacetal
precursor 7a-c. These have been coupled with chrysin to give 8a-c. These
nitrothioacetals 8a-c upon reduction with SnCl2.2H2O gives 9a-c, the
deprotection of diethyl thioacetal group afforded the desired compounds 10a-c
(Scheme 1).
V
Synopsis
Scheme 1
HO
HO
i
H
H3CO
HO
ii
OH
H3CO
O
O
1
OCH3
H3CO
O
3
2
iii
Br
O
n
NO2
v
OH
H3CO
Br
O
n
NO2
Br
iv
OCH3
H3CO
O
n
O
O
O
6a-c
OCH3
H3CO
4a-c
5a-c
vi
Br
O
n
NO2 CH(SEt)2
N
H3CO
O
O
O
n
vii
NO2 CH(SEt)2
N
H3CO
O
O
O
OH
7a-c
8a-c
viii
O
O
O
n
NH2 CH(SEt)2
N
H3CO
O
OH
9a-c
O
ix
O
O
O
n
N
N
H3CO
O
OH
H
O
10a-c
n=3,4,5
Reagents and conditions : i) NH2SO3H, NaClO2, H2O, 1 h, 72 %. ii) H2SO4, MeOH, 48 h, 98%.
iii) Br-(CH2)n-Br, K2CO3, CH3COCH3, reflux, 24 h, 90-93%. iv) HNO3-H2SO4, SnCl4, CH2Cl2, -25 oC, 5
min, 75-76%. v) 2N NaOH, 8 h, 95%. vi) SOCl2, C6H6, (2S)-pyrrolidine-2-carboxaldehyde diethyl
thioacetal, THF, Et3N, 0 oC, 3 h, 85-89%. vii) 5, 7-dihydroxyflavone, K2CO3, CH3COCH3, reflux, 24 h,
88-90%. viii) SnCl2.2H2O, MeOH, reflux, 40 min, 95-97%. ix) HgCl2-CaCO3, H2O:CH3CN (1:4), 8-12 h,
50-58%.
VI
Synopsis
The DNA binding ability for these chrysin-PBD hybrids have been
compared with Tm of DC-81. It is interesting to observe that all the three
compounds elevate the helix melting temperature of CT-DNA after incubation
for 18 h at 37 C. In this assay, compound 10a elevates the melting temperature to
8.8 C. Compound 10b elevates the melting temperature to 7.3 C, while the
compound 10c elevated the melting temperature to 6.7 C, whereas DC-81
exhibits aTm of 0.7 C after incubation under similar conditions. Thus, this
demonstrated that this class of PBD hybrids posses significant DNA binding
ability. The restriction endonuclease inhibition studies carried out on these
molecules also confirm the relative binding affinity of these new PBD hybrids.
Compounds 10a and 10c have been evaluated for their in vitro cytotoxicity
in selected human cancer cell lines of colon (Colo205), lung (Hop-62), cervix
(SiHa), prostate (DU145, PC3), oral (DWD, HT1080), and breast (MCF7, Zr-75-1)
origin. These compounds exhibited more than 20% growth inhibition at g/mL
concentration on these cell lines. Compounds 10a and 10c suppress MCF7 cell
growth by 40% and 37%. They also suppress the Zr-15-1 cell growth by 22% and
HT1080 cell growth by 30% and 26%.
Chapter II-Section B: Design, synthesis and biological evaluation of novel
quinazolinone-pyrrolo[2,1-c][1,4]benzodiazepine hybrids
Quinazolinone based compounds are well known for their broad
spectrum of biological activities, the most important among them being the
anticancer activity. The anticancer activity of these compounds has been
extensively studied, although the mechanism of action is not known, most of the
quinazolinones exert their antitumour activity either by tubulin inhibition or
PARP inhibition or as alkylating agents.
VII
Synopsis
In view of the importance of these quinazolinone derivatives for their
anticancer potential, it has been considered of interest to synthesize new
quinazolinone moieties that have been linked to the PBD ring system to evaluate
their DNA binding affinity and in vitro cytotoxicity.
Synthesis of these novel quinazolinone-PBD hybrids have been carried out
by employing substituted quinazolinones 12a-b as the precursors, which have
been obtained by the reaction of substituted 2-aminobenzophenone 11a-b with
chlorosulfonyl isocyanate to yield substituted quinazolinone 12a-b. These were
further treated with the appropriate n-bromo alkane to obtain the desired
intermediates 13a-c and 14a-c (Scheme 2).
Scheme 2.
R2
O
R2
R1
R2
i
R1
NH2
N
H
11a-b
12a-b
N
ii
N
O
O
N
R1
Br
n
n= 3,4,5
13a-c R1 = Cl, R2 = H
14a-c R1 = Cl, R2 = Cl
Reagents and conditions: i) chlorosulfonyl isocyanate, C6H6, 0-5o then rt, 3 h, 70-80 % yield.
ii)Br-(CH2)n-Br, K2CO3, MeCN, reflux, 24 h, 82-88% yield
The
other
precursor
(2S)-N-(4-hydroxy-5-methoxy-2-nitrobenzoyl)
pyrrolodine-2-carboxaldehyde diethyl thioacetal 21 has been prepared by
employing commercially available vanillin. Oxidation of vanillin followed by
esterification by literature method provides vanillin methyl ester 3. This on
benzylation gives 15, which upon nitration followed by ester hydrolysis affords
17. L-Proline methyl ester has been coupled to 17 to give the nitro ester 18. This
nitro ester on treatment with DIBAL-H followed by protection of aldehyde 19
with ethanethiol gives diethyl thioacetal 20. This upon debenzylation with
BF3.OEt2 provides compound 21. This nitro thioacetal has been coupled with the
corresponding substituted quinazolinones 13a-c and 14a-c to give 22a-c and 23a-
VIII
Synopsis
c. These nitrothioacetals 22a-c and 23a-c have been reduced with SnCl2.2H2O to
give 24a-c and 25a-c. The deprotection of the diethyl thioacetal group afforded
the desired products 26a-c and 27a-c (Scheme 3).
Scheme 3
HO
BnO
i
OCH3
H3CO
3
BnO
ii
OCH3
H3CO
O
15
NO2
OCH3
H3CO
O
16 O
iii
BnO
NO2 CHO
BnO
NO2 COOMe
v
N
H3CO
BnO
iv
N
H3CO
O
19
NO2
OH
H3CO
O
18
O
17
vi
R2
BnO
NO2 CH(SEt)2
H3CO
HO
NO2 CH(SEt)2
N
vii
N
N
H3CO
O
20
viii
O
N
O
n
O
R1
21
NO2 CH(SEt)2
N
H3CO
22a-c
23a-c
R2
O
N
R1
ix
R2
N
N
O
n
N
R1
N
H3CO
O
n = 3,4,5
O
N
x
H
O
O
n
NH2 CH(SEt)2
N
H3CO
24a-c
25a-c
O
26a-c R1 = Cl, R2 = H
27a-c R1 = Cl, R2 = Cl
Reagents and conditions: i) BnCl, 2N NaOH, THF, reflux, 48 h, 92%. ii) HNO3-H2SO4, SnCl4, CH2Cl2,- 25oC,
5 min,89%. iii) 2N LiOH, THF, MeOH, H2O(3:1:1), rt, 12 h,90%. iv) SOCl2, C6H6, L-proline methyester
hydrochloride, THF, Et3N, 0 oC, 3 h, 93%. v) DIBAL-H, CH2Cl2, -78oC, 45 min, 60%. vi) EtSH-TMSCl, CH2Cl2,
rt, 16 h, 85%. vii) BF3-OEt2-EtSH, CH2Cl2, 12 h, 90%. viii) K2CO3, CH3COCH3, reflux, 24 h, 80-82%. ix)
SnCl2.2H2O, MeOH, reflux, 40 min, 95-96%. x) HgCl2-CaCO3, H2O:CH3CN (1:4), 8-12 h, 55-60%.
IX
Synopsis
Compounds 26a and 26c have been evaluated for their in vitro cytotoxicity
in selected human cancer cell lines of colon (Colo205), lung (Hop-62), cervix
(SiHa), prostate (DU145, PC3), oral (DWD, HT1080), and breast (MCF7, Zr-75-1)
origin. These compounds have exhibited more than 80% growth inhibition at
g/mL concentration in some cell lines. Compounds 26a and 26c suppress Colon
205 cell growth by 92% and 85%, DU145 cell growth by 92% and 90%, DWD cell
growth by 95%, Hop62 cell growth by 94% and 95%, HT1080 cell growth by 91%
and 92%, MCF7 cell growth by 88% and 92% and PC3 cell growth by 89% and
93%. They are known for suppressing the SiHa cell growth by 84% and Zr-25-1
cell growth by 92% respectively.
The DNA binding ability for these quinazolinone-PBD hybrids have been
compared with Tm of DC-81. It is interesting to observe that in this assay the
compounds elevate the helix melting temperature of CT-DNA upto 1.3 C for
compound 26a, 1.6 C for compound 26b, 2.3 C for compound 26c, 0.8 C for
compound 27b and 1.0 C for compound 27c after incubation for 18 h at 37 C,
whereas DC-81 exhibits a Tm of 0.7
C
after incubation under similar
conditions. The compound 27a has shown a Tm of 0.5 C and the dichloro
substituted quinazolinones linked PBDs have shown less DNA binding affinity
than their monochloro substituted analogues. This variation might be due to the
presence of bulky chloro groups in case of the later compounds. As the spacer
length is increased the DNA binding affinity of these compounds is also
enhanced.
Chapter II-Section C: Design, synthesis and DNA binding affinity of novel
indolindione-PBD hybrids
Indolindione ring systems when coupled to various bioactive heterocycles
have drastically increased the activities of the heterocycles due to the
X
Synopsis
antiproliferative and alkylating properties. The derivatives of these compounds
have also exhibited promising anticancer activities on various cell lines.
In the present work it has been envisaged to link these indolindiones to
the PBDs with a view to combine the alkylating properties of PBDs with
alkylating and antiproliferative properties of indolindiones and to study their
DNA binding affinity. These compounds are under the process of evaluation of
their in vitro cytotoxicity.
Synthesis of these novel indolindione-PBD hybrids has been carried out
by employing 1-(n-bromoalkyl)-2,3-indolinedione 29a-c as one of the precursors,
which has been obtained by the reaction of 2,3-indolindione 28 with appropriate
n-bromo alkane to obtain the desired intermediates, which are coupled with (2S)N-(4-hydroxy-5-methoxy-2-nitrobenzoyl)pyrrolodine-2-carboxaldehyde
diethyl
thioacetal 21 to give 30a-c. This nitrothioacetal 30a-c has been reduced with
SnCl2.2H2O and on deprotection of the thioacetal group afforded the desired
products 31a-c (Scheme 4).
XI
Synopsis
Scheme 4
HO
NO2 CH(SEt)2
i
+
N
H3CO
N
O
O
n Br
O
29a-c
21
NH
O
O
28
ii
N
O
O
n O
NO2 CH(SEt)2
N
H3CO
30a-c
O
iii, iv
N
O
O
n O
N
H
N
H3CO
O
31a-c
n = 3, 4, 5
Reagents and coditions: i) 2,3-indolinedione,K2CO3, CH3CN, reflux, 24 h, 85-88 %. ii) K2CO3, CH3COCH3,
reflux, 18 h, 75-79%. iii) SnCl2.2H2O, MeOH, reflux, 40 min. iv) HgCl2-CaCO3, H2O:CH3CN (1;4), 8-12 h, 5055%.
The DNA binding ability for the indolindione-PBD hybrids have been
compared with Tm of DC-81. It is interesting to observe that in this assay the
compounds 31a, 31b and 31c elevate the helix melting temperature of CT-DNA
upto 1.2 C, 1.0 C, 0.9 C respectively after incubation for 18 h at 37 C, whereas
DC-81 exhibits a Tm of 0.7 C after incubation under similar conditions. Thus
demonstrating that these PBD hybrids possess moderate DNA binding ability.
XII
Synopsis
Chapter III: Design, synthesis and in vitro cytotoxicity of novel chrysin
conjugates
Naturally occurring chrysin has attracted the attention of medicinal
chemists due to its ability to exhibit cytotoxicity by interacting with the DNA
either by intercalation between the DNA base pairs or by inhibiting
topoisomerase II. Although many new analogues of chrysin have been designed
and synthesized, none of them have reached the clinical trails. In order to
enhance the anticancer properties of chrysin, various conjugates have been
designed, synthesized and evaluated for their anticancer activity on a number of
cell lines.
In this part of the work, synthesis of various types of chrysin conjugates
by linking them to other anticancer moieties that can interact with DNA have
been envisaged. A variety of chrysin conjugates with alkyl and piperazinylalkyl
spacers and anticancer heterocylces like the coumarins, anthraquinones and
chrysin dimers have been synthesized and evaluated for their anticancer
potential on various human tumor cell lines.
The synthesis of novel C7 linked aminoalkyl chrysin derivatives 39a-c,
40a-c and 41a-c has been carried out by employing phloroglucinol 32 as the
starting material, which is treated with methyl iodide in presence potassium
carbonate to give dimethoxy phenol 33. This compound is further acetylated to
give the corresponding acetophenone 34, which upon aldol condensation with
benzaldehyde gives the chalcone 35. This is cyclized using iodine in DMSO and
demethylated with BBr3 to give chrysin 37, which is further refluxed in acetone
with the corresponding dibromo alkanes and potassium carbonate to yield the
compounds 38a-c. This is further refluxed with corresponding amino alkyl base
in acetonitrile in presence of potassium carbonate to yield the desired products
(Scheme 5).
XIII
Synopsis
Scheme 5
HO
OH
H3CO
H3CO
OH
i
OH
ii
OH
32
CH3
OCH3 O
34
OCH3
33
iii
HO
H3CO
O
O
H3CO
v
OH
iv
H3CO
OH O
37
O
36
OCH3 O
35
vi
Br
O
n
O
vii
OH
R
O
n
O
O
OH
O
38a-c
39a-c,
R=
HN
NCH3
n = 3, 4, 5
40a-c,
R=
HN
O
n = 3, 4, 5
41a-c,
R=
HN
n = 3, 4, 5
Reagents and conditions: i) CH3I, K2CO3, CH3COCH3, reflux, 3 h, 20%yield ii) CH3COCl, AlCl3, CH2Cl2,
0oC-rt, 1h, 60% yield iii) benzaldehyde, KOH, MeOH, rt, 80%yield iv) I2, DMSO, heat, 70%yield v) BBr3,
CH2Cl2, 0oC-rt, 80%yield vi) Br-(CH2)n-Br, K2CO3, CH3COCH3, reflux, 6 h, 85-90% yield vii) K2CO3,
CH3CN, for compound 8a-c, 1-methylpiperazine; for compound 9a-c, morpholine; for compound 10a-c,
NN-diethylamine, reflux, 6 h, 85-90% yield.
The precursors, alkylbromo linked piperazinyl coumarins, have been
synthesized by employing 2-hydroxy acetophenone 42 as the starting material,
which is cyclized to give hydroxy coumarin 43. This upon treatment with
XIV
Synopsis
piperazine yields the piperazinyl coumarin 44. This is refluxed with dibromo
alkane in acetonitrile in presence of potassium carbonate to give the desired
precursors 45a-c. This upon further treatment with chrysin yields the
corresponding products 46a-c (Scheme 6).
Scheme 6
OH
i
O
O
O
ii
O
O
O
iii
CH3
O
42
OH
43
N
N
N
H
44
N
nBr
45a-c
iv
O
O
N
N
O
n
O
OH O
46a-c
n = 3, 4, 5
Reagents and conditions: (i) Na, diethyl carbonate, 4 h, reflux, 70-75%. (ii) piperazine, 1 h, 160 0C,
75-80%. (iii) nBr-(CH2)-Br, K2CO3, CH3CN, 24 h, reflux, 80-90%. (iv) 5,7-dihydroxy flavone, K2CO3,
8 h, reflux, 80-90%
Synthesis of novel anthraquinone chrysin conjugates has been carried out
by employing N1-(9,10-dioxo-9,10-dihydro-1-anthracenyl)-n-bromoalkanamide
48a-b as precursors, that have been obtained by the reaction of an appropriate
acid chloride with 1-amino anthraquinone 47 (Scheme 7).
XV
Synopsis
Scheme 7
O
O
NH2
O
HN
n
Br
i
O
n = 2, 3
O
47
48a-b
Reagents and conditions: i) Br-(CH2)n-COCl, C5H5N, C7H8, reflux, 2 h
The compounds 49a-b have been prepared by refluxing the precursor N1(9,10-dioxo-9,10-dihydro-1-anthracenyl)-n-bromoalkanamide 48a-b along with
chrysin 37 and potassium carbonate in acetone (Scheme 8).
Scheme 8
O
O
HN
Br
n
HO
i
+
O
48a-b
O
O
O
HN
O
O
n
OH O
OH O
37
n = 2, 3
O
49a-b
Reagents and conditions: i) K2CO3, CH3COCH3, reflux, 6 h, 80% yield
5-Hydroxy-7-n-[(5-hydroxy-4-oxo-2-phenyl-4H-7-chromenyl)oxy]alkoxy2-phenyl-4H-4-chromenone 50a-c have been prepared by refluxing chrysin 37
with the corresponding dibromo alkanes (Scheme 9).
XVI
Synopsis
Scheme 9
HO
O
O
O
O
n
i
O
OH O
37
OH
O
OH O
50a-c
n = 3, 4, 5
Reagents and conditions: i) Br-(CH2)n-Br, K2CO3, CH3COCH3, reflux, 12 h, 75%yield
5-Hydroxy-7-[n-(4-n-[(5-hydroxy-4-oxo-2-phenyl-4H-7-chromenyl)oxy]
alkylpiperazino)alkoxy]-2-phenyl-4H-4-chromenones 51a-c have been prepared
by treating 7-[(n-bromoalkyl)oxy]-5-hydroxy-2-phenyl-4H-4-chromenone 38a-c
with piperazine (Scheme 10).
Scheme 10
Br
O
n
O
O
O
n
i
OH O
38a-c
O
OH
N
N
O
n
51a-c
O
OH O
n = 3, 4, 5
Reagents and conditions: i) piperazine, K2CO3, CH3COCH3, reflux, 12 h, 85-89% yield
The above novel chrysin conjugates have been initially screened for their
in vitro cytotoxicity on three human tumor cell lines comprising of MCF7
(breast), NCI-H460 (lung) and SF-268 (CNS). The compounds 39a, 39c, 40a, 40c,
41a, 46a which have shown 0% cell growth have been selected for further
evaluated in the standard NCI 60 cell line panel. The compounds have shown to
possess less than 10 nanomolar potency (at the LC50 level) against nine cell lines
of one non-small-cell lung cancer cell line (NCI-H522), one CNS cancer cell line
(SF-539), three melanoma cancer cell lines (SK-MEL-2, SK-MEL-5, UACC-62 and
M14) two renal cancer cell lines (A 498 and RXF 393) and one breast cancer cell
line (MDA-MB-435). Interestingly, these compounds possess selective anticancer
activity.
XVII
Synopsis
Chapter IV: NaI-AcOH: A versatile reagent system in organic synthesis
Sodium iodide in combination with various other organic, inorganic
reagents and solvents has been extensively used for different chemical
transformations in high yields.
In view of the importance of sodium iodide in organic synthesis a new
reagent system i.e., a combination of sodium iodide and acetic acid has been
developed and employed towards the synthesis of various bioactive heterocycles
by azidoreductive cyclocondensation process as discussed below. Sodium iodide
in combination with organic acids (acetic acid, formic acid) has also been
employed for the N-acylation of aromatic azides.
The commercially available substituted anthranillic acid was treated with
sodium acetate, sodium nitrite and sodium azide to yield the substituted 2azidobenoic acid 53a-c, upon treatment with the corresponding lactams provide
N-(2-azidobenzoyl)-lactams 54a-i. These compounds are further treated with
sodium iodide in acetic acid (Scheme 11) to yield the corresponding fused[2,1-b]
quinazolinones 55a-i.
Scheme 11.
R1
R2
NH2
OH
O
52a-c
i
R1
R2
N3
ii
R1
N3 O
OH
N
R2
O
53a-c
n
O
54a-i
iii
R1
R2
N
N
O
55a-i
Reagents and conditions: i) NaNO3, NaOAc, NaN3, rt, 2h; ii) 2-pyrrolidinone or 2piperidinone or 2-azepinone, SOCl2, Et3N, THF, rt, 5h; iii) Sodium iodide, acetic acid,
reflux, 3h.
XVIII
n
Synopsis
Further, N-substituted imides have been synthesized by the reductive
cyclocondensation process by the treatment the corresponding anhydrides or
acids with the respective azides (Scheme 12) in presence of sodium iodide in
acetic acid.
Scheme 12.
O
O
O
or
O
56a-58a
56 =
O
OH
OH
i
NR
O
59a-d
60a-d
61a-b
O
56b-58b
58 =
57 =
Reagents and conditions: i) alkyl or aryl azides, sodium iodide, acetic acid,
reflux, 3-6.5 h, 50-85% yield
DNA intercalating naphthalimide dimers linked by alkyl spacers and
piperazinyl alkyl spacers have been synthesized by refluxing the naphthalic
anhydride or naphthalic acid and the respective diazide in presence of sodium
iodide in acetic acid (Scheme 13) until the TLC indicated the completion of the
reaction. The products were obtained in good to moderate yields.
XIX
Synopsis
Scheme 13
O
O
O
OH
OH
or
O
57b
57a
O
N3
N3
N3
n
n
N
n
n
N
O
O
O
62a-c
n
N3
O
O
N
N
i
i
O
N
O
N
N
N
n
62d-f
O
n = 0, 1, 2
n = 1, 2, 3
Reagents and conditions: i) Sodium iodide, acetic acid, reflux, 10-12 h, 70-92 % yield.
Quinazolindione derivatives 64a-e have been synthesized in good yields
from the isatoic anhydride 63 and the corresponding azide (Scheme 14).
Scheme 14
O
O
i
O
N
H
63
N
R
N
O
H
64a-e
O
Reagents and conditions: i) aryl azide, sodium iodide, acetic acid, reflux,
5 h, 52-95 % yield
Naphthalimide linked PBD-5,11-diones have been synthesized by
employing compounds 65a-c as the starting materials. This nitro precursor upon
treating with sodium azide in HMPA at room temperature produces 66a-c. The
azido compounds 66a-c upon heating in presence of sodium azide and DMSO
XX
Synopsis
yield 67a-c. These upon reductive cyclocondensation in one pot afford the
desired products 68a-c in good yields (Scheme 15).
Scheme 15
COOCH3
NO2
O
Br
n
COOCH3
N3
n
i
N
H3CO
O
Br
N
H3CO
O
O
65a-c
66a-c
ii
O
O
N
H
N
O
H
n
O
O
N3
O
N3
COOCH3
n
N
H3CO
N
H3CO
68a-c
iii
O
67a-c
n = 1, 2, 3
Reagents and conditions: i) NaN3, HMPA, rt, 6 h; ii) NaN3, DMSO, , 1 h; iii) sodium iodide, acetic acid,
naphthalic anhydride or naphthalic acid, reflux, 12 h.
Sodium iodide in presence of the organic acids namely, acetic acid or
formic acid has been employed towards the reduction of azides to their
corresponding acetamides or formamides (Scheme 16). The products were
obtained in good to moderate yields.
Scheme 16
H
N
N3
R2
R1
69
R2
R1
70a-h
R
O
Reagents and conditions : i) NaI, CH3COOH or HCOOH, reflux, 3-4 h
XXI