Design, synthesis and in vitro anticancer evaluation of 4,6-diamino-1,3,5-triazine-2-carbohydrazides and -carboxamides

Article abstract of DOI:10.1016/j.bmcl.2013.09.087

Series of substituted 4,6-diamino-1,3,5-triazine-2-carbohydrazides and -carboxamides have been synthesised, based on molecular modelling of candidate structures related to the previously reported Rad6B-inhibitory diamino-triazinylmethyl benzoate anticance

Full text of DOI:10.1016/j.bmcl.2013.09.087

Bioorganic & Medicinal Chemistry Letters xxx (2013) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design, synthesis and in vitro anticancer evaluation
of 4,6-diamino-1,3,5-triazine-2-carbohydrazides and -carboxamides
Hend Kothayer a,b, Abdalla A. Elshanawani b, Mansour E. Abu Kull b, Osama I. El-Sabbagh b,c
,
Malathy P. V. Shekhar d, Andrea Brancale a, Arwyn T. Jones a, Andrew D. Westwell a,
⇑
a School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff CF10 3NB, Wales, UK
b Faculty of Pharmacy, Zagazig University, Egypt
c Faculty of Pharmacy, Taif University, Taif, Saudi Arabia
d Karmanos Cancer Institute, 110 E. Warren Avenue, Detroit, MI 48201, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Series of substituted 4,6-diamino-1,3,5-triazine-2-carbohydrazides and -carboxamides have been
synthesised, based on molecular modelling of candidate structures related to the previously reported
Rad6B-inhibitory diamino-triazinylmethyl benzoate anticancer agents TZ8 and TZ9. Synthesis of the
target compounds was readily accomplished in two steps from aryl biguanides via reaction of
phenylhydrazine or benzylamines with key 4-amino-6-(arylamino)-1,3,5-triazine-2-carboxylate
intermediates. These new triazine derivatives were tested for in vitro anticancer activity against the
Rad6B expressing human breast cancer cell lines MDA-MB-231 and MCF-7. Active compounds, such as
the triazinyl-carbohydrazides 3a–e, were found to exhibit low micromolar IC50 values particularly in
the Rad6B-overexpressing MDA-MB-231 cell line.
Received 6 September 2013
Revised 26 September 2013
Accepted 27 September 2013
Available online xxxx
Keywords:
E2 ubiquitin conjugating enzyme
Rad6B
Triazines
Breast cancer
MDA-MB-231
MCF-7
Ó 2013 Published by Elsevier Ltd.
The highly-regulated ubiquitin-proteasome system, responsible
for degradation of >80% of cellular proteins, has proven to be a pop-
ular target for the development of new anticancer agents in recent
years.1 Research in this field has culminated in the clinical approval
of bortezomib (VelcadeÒ) as the first-in-class small molecule
proteasome inhibitor for treatment of relapsed multiple myeloma
and mantle cell lymphoma.1 A major function of the protein
ubiquitination system serves to polyubiquitinate (tag with small
proteins) cellular proteins destined for proteasomal degradation.2
However the role of ubiquitination in other important cellular
functions such as cell signalling and DNA repair is now becoming
more widely appreciated.3 Three successive classes of enzymes of
increasing structural and mechanistic class diversity mediate
protein ubiquitination. The process starts with the ubiquitin-
activating enzyme (E1) that forms a thioester bond between its
active site cysteine and the carboxyl terminus of the ubiquitin
protein. Transfer of ubiquitin to the family of thioester-linked E2
ubiquitin conjugating enzymes results in either direct transfer of
ubiquitin to the protein substrate, or interaction with the larger
family of E3 ubiquitin–protein ligases resulting in substrate
mono- or poly-ubiquitination.
Extensive efforts in recent years to target various classes of E3
ubiquitin ligases deregulated in cancer cells has led to the develop-
ment of a number of potential cancer therapeutics. Amongst the
most well developed examples are the Mdm2 (E3 ligase)—p53 pro-
tein–protein interaction inhibitors known as the Nutlins, currently
being studied in clinical trials for cancer.4 A further example is pro-
vided by the disulfiram-based inhibitors of the E3 ligase enzyme
BCA2 (breast cancer associated protein-2) discovered in our
laboratories.5
Inhibitors of E2 ubiquitin conjugating enzymes are less well
studied than their E3 counterparts, despite their potential as can-
cer drug targets in a number of cases. For example, the E2 enzyme
Rad6B has been found to be essential for post-replication DNA
repair, and Rad6B over-expression is reported in breast cancer cell
lines and tumours. Constitutive Rad6B over-expression in non-
transformed cells is associated with induction of cancer pheno-
typic changes including centrosome amplification, abnormal
mitosis and aneuploidy.6 The ability of Rad6B to ubiquitinate
b-catenin leads to conjugates insensitive to proteasomal degrada-
tion. Consequent stabilisation and activation of oncogenic b-cate-
nin provides further evidence of the therapeutic potential of
Rad6B as a drug target, particularly in breast cancer.7,8
An important therapeutic advance in this area was the recent
report from our laboratories of the first selective inhibitors of
⇑
Corresponding author. Tel.: +44 (0)2920 875800; fax: +44 (0)2920 874149.
E-mail address: WestwellA@cf.ac.uk (A.D. Westwell).
0960-894X/$ - see front matter Ó 2013 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.bmcl.2013.09.087
Please cite this article in press as: Kothayer, H.; et al. Bioorg. Med. Chem. Lett. (2013), http://dx.doi.org/10.1016/j.bmcl.2013.09.087

2
H. Kothayer et al. / Bioorg. Med. Chem. Lett. xxx (2013) xxx–xxx
R
were studied by docking candidate compounds onto a published
Cl
human Rad6B protein crystal structure (PDB ID: 2YB6).15,16 For
docking studies, we used the Rad6B active site template previously
defined for triazines TZ8 and TZ9, based on minimum docking
scores and binding energy orientations of test ligands.9 Molecular
docking interactions with structure 2YB6 were studied using
MOE17 and the LeadIt molecular docking software.18 Compounds
showing the lowest docking scores and binding energy interactions
were selected for synthesis and anticancer evaluation. For example
the triazine carbohydrazide derivative (3c) was incorporated deep
inside the Rad6B binding pocket, making key interactions between
the hydrazine nitrogen atoms and the Rad6B active site residues
Cys88 and Asp90. Additional interactions between the anilino
nitrogens of 3c and Asn119/Gln93, and between the phenyl (hydra-
zide) ring and Leu89 were also apparent from our docking analysis
(Fig. 2). The importance of these active site residues to the allosteric
effect on Rad6B induced by E3 ligases, and the observation that no
other E2 family members (with the exception of Rad6A) have resi-
dues corresponding to Gln93 or Asn119, suggest that these triazine
carbohydrazides could be selective Rad6B inhibitors. In contrast our
docking analysis suggested that the corresponding triazine carbox-
amides such as 6c would be able to form hydrogen bonds with ac-
tive site residues Cys88 and Asp90, but would fail to make
additional interactions with other active site residues such as
Leu89, Asn119 and Gln93 (see Supplementary information for addi-
tional docking interaction maps of triazines 3c and 6c).
The synthesis of the 4-amino-6-(arylamino)-N-phenyl-1,3,5-tri-
azine-2-carbohydrazides (3a–e) was accomplished in two steps
from arylbiguanide hydrochloride salts (1a–e), which were
prepared from commercially available substituted aniline and
dicyandiamide according to previously reported proedures.9,12
Neutralisation of the arylbiguanide hydrochloride salt using
sodium methoxide/methanol was followed by reaction with
dimethyloxalate in refluxing methanol to give the intermediate
methyl 4-amino-6-(arylamino)-1,3,5-triazine-2-carboxylates (2a–
e) in 83–92% isolated yield following recrystallisation from meth-
anol.19 Reaction of intermediates (2a–e) with phenylhydrazine in
refluxing ethanol, catalysed by glacial acetic acid, produced the
target triazine carbohydrazides (3a–e)20,21 in high yield (91–96%)
following recrystallisation from methanol (Scheme 1).
O
N
Cl
O
NO2
N
N
N
H2N
N
N
H
H2N
N
NH2
Irsogladine
(anti-ulcer)
TZ8 (R=Me)
TZ9 (R=H)
(Rad6B-inhibitory
anticancer)
Figure 1. Biologically active tri-substituted 1,3,5-triazine derivatives.
Rad6B ubiquitin conjugating enzyme.9 Virtual screening of a li-
brary of drug-like structures against a pharmacophore model gen-
erated from the conserved key residues stabilizing the E2-ubiquitin
thioester intermediate, identified a substituted diamino-triazine
core structure as a starting point for analogue synthesis. Triazine
analogue synthesis coupled to in vitro anticancer evaluation in
Rad6B-relevant models led to the identification of (4-amino-6-
(arylamino)-1,3,5-triazin-2-yl)methyl 4-nitrobenzoates TZ8 and
TZ9 (Fig. 1) as novel and selective Rad6B-inhibitory anticancer lead
compounds.9
The tri-substituted 1,3,5-triazine scaffold plays an important
role in medicinal chemistry, since a number of triazine based com-
pounds are reported to possess useful biological properties. Biolog-
ically active tri-substituted triazines include the anti-gastric ulcer
agent irsogladine (Fig. 1),10 commonly used in Japan and also
shown to possess anti-angiogenic/anti-metastatic activity;11 plus
other agents with anticancer,12 antimalarial,13 and antimicro-
bial14a,b properties. In this Letter, we detail the design, synthesis
and in vitro anticancer evaluation of new 4-amino-6-(arylamino)-
N-phenyl-1,3,5-triazine-2-carbohydrazides and related carboxam-
ides, derived from our previous lead compounds TZ8 and TZ9.
A key limitation of the previously identified (4,6-diamino-1,3,5-
triazin-2-yl)methyl benzoate derivatives TZ8 and TZ9 was their dif-
ficult and rather unreliable synthesis. Reaction of arylbiguanide and
ethyl glycolate in particular proceeded in poor yield, accompanied
by a number of by-products arising from the unprotected glycolate
function.9 We therefore studied the possibility of inverting the ester
function to obtain compounds with similar promising anticancer
activity via Rad6B inhibition using a molecular modelling approach
to guide new compound design. New derivatives of TZ8 and TZ9
A similar strategy was adopted for synthesis of new 4-amino-6-
(arylamino)-N-benzyl-1,3,5-triazine-2-carboxamides (6a–d). In
this case, arylbiguanides (1a and b) were cyclised with diethylox-
alate in refluxing ethanol to generate the intermediate triazine
Figure 2. Docking interactions of triazine carbohydrazide 3c and triazine carboxamide 6c in the Rad6B active site.
Please cite this article in press as: Kothayer, H.; et al. Bioorg. Med. Chem. Lett. (2013), http://dx.doi.org/10.1016/j.bmcl.2013.09.087

H. Kothayer et al. / Bioorg. Med. Chem. Lett. xxx (2013) xxx–xxx
3
H
N
O
N
OCH3
N
O
N
N
H
NH
NH
(i), (ii)
(iii)
N
.HCl
NH2
R
R
R
N
N
N
N
NH2
N
H
N
NH2
H
H
H
2a-e
3a-e
1a-e
R
a
H
b
c
4-OMe
4-Me
d
2-OMe
e
4-Cl
Scheme 1. Synthesis of 4-amino-6-(arylamino)-N-phenyl-1,3,5-triazine-2-carbohydrazides (3a–e). Reagents and conditions: (i) NaOCH3, CH3OH, rt, 3 h; (ii) dimethyloxalate,
CH3OH, reflux, 4 h; (iii) phenylhydrazine, AcOH, EtOH, reflux, 12 h.
H
O
N
OCH2CH3
NH2
R'
O
N
N
R
R
R'
R
R
R'
NH
NH
(i), (ii)
(iii)
N
+
N
.HCl
NH2
a
b
c
H
H
H
OMe
N
N
N
N
NH2
N
N
NH2
OMe OMe
OMe
H
H
R, R'
H
H
d
H
5a-b
6a-d
1a-b
4a-b
a
b
H
OMe
Scheme 2. Synthesis of 4-amino-6-(arylamino)-N-benzyl-1,3,5-triazine-2-carboxamides (6a–d). Reagents and conditions: (i) NaOCH3, CH3OH, rt, 3 h; (ii) diethyloxalate,
ethanol, reflux, 18 h; (iii) AcOH, dioxane, reflux, 18 h.
Table 1
ethyl esters (4a and b) in 70–79% yield. Reaction of intermediates
4a and b with benzylamines (5a and b) in dioxane under reflux,
catalysed by acetic acid, produced the required triazine carboxam-
ides (6a–d)22,23 in good yield (62–74%) after recrystallisation from
methanol (Scheme 2).
Growth inhibitory activity (IC50, lM) values in human breast cancer cell lines MDA-
MB-231 and MCF-7, and the non-transformed epithelial cell line MCF10A, using the
CTB assay (72 h incubation with test compound)
Compound
MDA-MB-231
MCF-7
MCF10A
3a
3b
3c
3d
3e
6a
6b
6c
3.67 (0.46)
4.79 (0.40)
4.65 (0.13)
2.71 (0.21)
2.48 (0.72)
145.7 (8.5)
>100
31.3 (3.1)
38.0 (2.5)
16.6 (0.2)
53.2 (4.8)
25.5 (5.2)
114.2 (6.2)
101.2 (15.0)
1.97 (0.72)
NT
>100
>100
>100
>100
>100
>100
>100
>100
Evaluation of newly synthesized 4-amino-N-phenyl-6-(aryla-
mino)-1,3,5-triazine-2-carbohydrazides (3a–e) and 4-amino-N-
benzyl-6-(arylamino)-1,3,5-triazine-2-carboxamides (6a–d) was
carried out in human breast cancer cell lines MDA-MB-231 and
MCF-7 using the CellTiter-BlueÒ (CTB) assay to assess cell viability,
as previously described (see Supplementary data).24 The standard
clinical anticancer drug doxorubicin and experimental proteasome
inhibitor N-(benzyloxycarbonyl)-leucinylleucinylleucinal (MG-
132)25 were also tested for comparative purposes. MDA-MB-231
is an established metastatic Rad6B over-expressing breast cancer
cell line, previously used in our studies on TZ8 and TZ9 analogues.9
The established MCF-7 breast cancer cell line has also previously
been used to study cellular effects of induced Rad6B.26 Anti-prolif-
erative data, expressed as mean values following testing on at least
three separate occasions, are presented in Table 1. Activity of com-
pounds in the nontransformed human breast epithelial cell line
MCF10A was also studied using the CTB endpoint assay.
32.9 (4.0)
>100
6d
NT
Doxorubicin ÅHCl
MG-132
TZ8
0.39 (0.19)
0.18 (0.02)
25a
0.075 (0.006)
0.13 (0.03)
NT
1.11 (0.14)
0.29 (0.01)
>100
TZ9
6a
NT
>100
Results are expressed as triplicate mean values (standard deviation in parentheses);
NT = not tested.
a
Approximate values due to low solubility in media.9
and in the case of 6a and 6b were also inactive in MCF-7 cells. In
contrast 4-amino-N-(2-methoxybenzyl)-6-(2-methoxy-phenyla-
mino)-1,3,5-triazine-2-carboxamide (6c) was found to be the most
active compound tested against the MCF-7 cell line (IC50 1.97
with moderate activity against MDA-MB-231 (IC50 32.9 M). All
The results presented in Table 1 indicate structure–activity rela-
tionship trends. In general the Rad6B-expressing MDA-MB-231 cell
line was the most sensitive to the effects of triazine hydrazide test
compounds (3a–e) with IC50 values in the low micromolar range
lM),
l
(2.48–4.79
l
M) for compounds of this type. These values compare
newly tested compounds were less active than the anticancer
drugs doxorubicin and MG-132. However it should be noted that
these standard agents were found to exhibit inhibitory activity in
the nontransformed breast epithelial cell line MCF10A (IC50 values
of 1.11 and 0.29 lM for doxorubicin and MG-132, respectively),
indicative of general toxicity. In contrast none of our newly synthe-
favourably with studies on TZ8 and TZ9 published previously,9
although it should be noted that the values for the previously de-
scribed triazines are compromised by poor solubility in tissue cul-
ture media. IC50 values for triazine hydrazides in the MCF-7 breast
cancer cell line were found to be in the range between 17 and
53
lM. For the triazine carboxamides compounds 6a, 6b and 6d
sized test triazines achieved an IC50 value over the concentration
were found to be essentially inactive in the MDA-MB-231 cell line;
range, giving IC50 values of >100 lM for the MCF10A cell line.
Please cite this article in press as: Kothayer, H.; et al. Bioorg. Med. Chem. Lett. (2013), http://dx.doi.org/10.1016/j.bmcl.2013.09.087

4
H. Kothayer et al. / Bioorg. Med. Chem. Lett. xxx (2013) xxx–xxx
13. Agarwal, A.; Srivastava, K.; Puri, S. K.; Chauhan, P. M. S. Bioorg. Med. Chem. Lett.
In summary, the computational design and synthesis of a series
2005, 15, 531.
of 4-amino-6-(arylamino)-N-phenyl-1,3,5-triazine-2-carbohydra-
zides and 4-amino-6-(arylamino)-N-benzyl-1,3,5-triazine-2-car-
boxamides as potential anticancer agents targeting Rad6B has led
to the discovery of a number of compounds with low micromolar
IC50 activity specifically in Rad6B expressing human cancer cell
lines. The triazine carbohydrazides (3a–e) were identified as the
most active compounds of the series in MDA-MB-231 cells, and
triazine carboxamide 6c was the most active compound against
MCF-7 cells. Our molecular modelling studies and cell line activity
profile are consistent with Rad6B as a potential mechanistic target
underpinning in vitro anticancer activity.
14. (a) Solankee, A.; Kapadia, K.; Ciric, A.; Sokovic, M.; Doytchinova, I.; Geronikaki,
A. Eur. J. Med. Chem. 2010, 45, 510; (b) Patel, R. V.; Kumari, P.; Rajani, D. P.;
Pannecouque, C.; De Clercq, E.; Chikhalia, K. H. Future Med. Chem. 2012, 4, 1053.
15. Hibbert, R. G.; Huang, A. D.; Boelens, R.; Sixma, T. K. Proc. Natl. Acad. Sci. U.S.A.
2011, 108, 5590.
16. Research Collaboratory for Structural Bioinformatics (RCSB) Protein Data Bank
(PDB). http://www.rcsb.org/pdb.
17. Molecular Operating Environment (MOE). Chemical Computing Group, Inc.
Montreal, Quebec, Canada. http://www.chemcomp.com.
18. BioSolveIT GmbH. http://www.biosolveit.de/LeadIT.
19. General method for synthesis of methyl 4-amino-6-(arylamino)-1,3,5-triazine-2-
carboxylates.
A
mixture of 1-arylbiguanide (1a–e, 60 mmol) and
dimethyloxalate (7.0 g, 60 mmol) in methanol (100 mL) was stirred at room
temperature under nitrogen for 2 h, and then heated under reflux for a further
4 h. The reaction mixture was allowed to cool, and the product crystals that
formed were collected under vacuum and washed with a small quantity of cold
methanol. Recrystallisation from methanol provided the product carboxylates
(2a–e) in 83–92% yield which was used without further purification in the next
step.
Acknowledgements
The authors are grateful to the Higher Education Ministry of the
Arab Republic of Egypt for the award of a Channel Scholarship (to
H.K.). We thank the EPSRC National Mass Spectrometry Centre
(Swansea, UK) for provision of accurate mass spectrometric
analysis.
20. General method for synthesis of triazine carbohydrazides (3a–e). Phenylhydrazine
(0.98 mL, 10 mmol) was added to a solution of the triazine ester intermediate
(2a–e, 5 mmol) in ethanol (50 mL) containing glacial acetic acid (ca. 10 drops).
The reaction mixture was heated under reflux for 12 h, then allowed and
allowed to stand overnight. The resulting crystals were collected by vacuum
filtration, dried and recrystallised from methanol to afford the triazine
carbohydrazide products (3a–e) in 91–96% yield.
Supplementary data
21. Representative characterization data: 4-amino-N-phenyl-6-(tolylamino)-1,3,5-
triazine-2-carbohydrazide (3c): (95% yield). Mp 210–212 °C. 1H NMR (DMSO-
d6) d 2.27 (3H, s, CH3), 6.75 (1H, t, J 7.8, H-40), 6.80 (2H, d, J 8.0, H-20, H-60), 7.11
(2H, d, J 8.0, H-2, H-6), 7.18 (2H, t, J 7.8, H-30, H-50), 7.36 (2H, bs, NH2), 7.69 (2H,
d, J 8.0, H-3, H-5), 7.95 (1H, s, NH), 9.75 (1H, bs, NH), 10.06 (1H, s, NH). 13C NMR
(DMSO-d6) d 20.40 (CH3), 112.24 (ArCH), 118.70 (ArCH), 120.22 (ArCH), 128.68
(ArCH), 128.85 (ArCH), 131.41 (ArC), 136.82 (ArC), 148.79 (ArC), 163.58 (ArC),
164.15 (ArC), 166.63 (ArC), 166.86 (ArC). MS (ESI+) 336.2 (M++1). Anal. Calcd
for C17H17N7O: C, 60.88; H, 5.11; N, 29.24. Found: C, 60.70; H, 4.91; N, 29.13.
22. General method for synthesis of triazine carboxamides (6a–c). A mixture of the
triazine ester intermediate (5a and b, 2 mmol), (substituted)benzylamine
(3 mmol), and glacial acetic acid (ca. 10 drops) in dioxane (30 mL) was heated
under reflux for 18 h. The reaction mixture was allowed to cool then
concentrated in vacuo and the residue poured onto ice. The resulting
precipitate was collected by vacuum filtration, dried and recrystallised from
methanol to afford the triazine carboxamide products (6a–c) in 62–74% yield.
23. Representative characterisation data: 4-amino-N-(2-methoxybenzyl)-6-(4-
methoxyphenylamino)-1,3,5-triazine-2-carboxamide (6c): (74% yield). Mp 145–
147 °C. 1H NMR (DMSO-d6) d 3.74 (3H, s, OCH3), 3.83 (3H, s, OCH3), 4.42 (2H, d,
J 6.1, CH2N), 6.87 (2H, d, J 9.1, H-3, H-5), 6.93 (1H, t, J 8.2, H-50), 7.03 (1H, d, J
8.1, H-30), 7.22 (1H, t, J 6.3, H-40), 7.29 (3H, m, H-60+NH2), 7.65 (2H, d, J 9.1, H-2,
H-6), 8.51 (1H, t, J 7.6, CONH), 9.72 (1H, bs, NH). 13C NMR (DMSO-d6) d 37.84
(CH2N), 55.17 (OCH3), 55.41 (OCH3), 110.65 (ArCH), 113.66 (ArCH), 120.19
(ArCH), 121.79 (ArCH), 126.02 (ArC), 127.96 (ArCH), 128.40 (ArCH), 132.40
(ArC), 154.91 (ArC), 156.81 (ArC), 162.82 (ArC), 164.26 (ArC), 165.77 (ArC),
167.03 (ArC). MS (ESI+) 381.2 (M++1). Anal. Calcd for C19H20N6O3: C, 59.99; H,
5.30; N, 22.09. Found: C, 60.00; H, 5.17; N, 21.79.
Supplementary data (Molecular modeling methodology and
Rad6B interaction maps with triazines 3c and 6c; full compound
characterisation data (mp, 1H, 13C NMR spectroscopy, mass spec-
trometry, % CHN analysis); cell culture protocols) associated with
this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.bmcl.2013.09.087.
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