Synthesis of novel tryptanthrin derivatives as dual inhibitors of indoleamine 2,3-dioxygenase 1 and tryptophan 2,3-dioxygenase

Article abstract of DOI:10.1016/j.bmcl.2020.127159

Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) are promising drug development targets due to their implications in pathologies such as cancer and neurodegenerative diseases. The search for IDO1 inhibitor has been intensely pursued but there is a paucity of potent TDO and IDO1/TDO dual inhibitors. Natural product tryptanthrin has been confirmed to bear IDO1 and/or TDO inhibitory activities. Herein, twelve novel tryptanthrin derivatives were synthesized and evaluated for the IDO1 and TDO inhibitory potency. All of the compounds were found to be IDO1/TDO dual inhibitors, in particular, compound 9a and 9b bore IDO1 inhibitory activity similar to that of INCB024360, and compound 5a and 9b had remarkable TDO inhibitory activity superior to that of the well-known TDO inhibitor LM10. This work enriches the collection of IDO1/TDO dual inhibitors and provides chemical molecules for potential development into drugs.

Full text of DOI:10.1016/j.bmcl.2020.127159

Bioorganic&MedicinalChemistryLettersxxx(xxxx)xxxx
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Bioorganic & Medicinal Chemistry Letters
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Synthesis of novel tryptanthrin derivatives as dual inhibitors of indoleamine
2,3-dioxygenase 1 and tryptophan 2,3-dioxygenase
Yuanyuan Lia, Shengnan Zhangb, Rong Wanga, Menghan Cuia, Wei Liuc, Qing Yangb,
⁎
Chunxiang Kuanga,
a Shanghai Key Lab of Chemical Assessment and Sustainability, School of Chemical Science and Engineering, Tongji University, 1239 Siping Road, 200092 Shanghai, China
b State Key Laboratory of Genetic Engineering, Department of Biochemistry, School of Life Sciences, Fudan University, 2005 Songhu Road, 200438 Shanghai, China
c School of Pharmacy, Nantong University, 19 Qixiu Road, 226001 Nantong, China
A R T I C L E I N F O
A B S T R A C T
Keywords:
Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) are promising drug development
targets due to their implications in pathologies such as cancer and neurodegenerative diseases. The search for
IDO1 inhibitor has been intensely pursued but there is a paucity of potent TDO and IDO1/TDO dual inhibitors.
Natural product tryptanthrin has been confirmed to bear IDO1 and/or TDO inhibitory activities. Herein, twelve
novel tryptanthrin derivatives were synthesized and evaluated for the IDO1 and TDO inhibitory potency. All of
the compounds were found to be IDO1/TDO dual inhibitors, in particular, compound 9a and 9b bore IDO1
inhibitory activity similar to that of INCB024360, and compound 5a and 9b had remarkable TDO inhibitory
activity superior to that of the well-known TDO inhibitor LM10. This work enriches the collection of IDO1/TDO
dual inhibitors and provides chemical molecules for potential development into drugs.
Novel tryptanthrin derivative
IDO1 inhibitor
TDO inhibitor
IDO1/TDO dual inhibitor
Water solubility
The kynurenine pathway (KP) is the major route of metabolism of
the essential amino acid L-tryptophan (Trp), degrading ~95% of the
dietary Trp into nicotinamide adenine dinucleotide (NAD).1 In-
doleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase
(TDO) initiate the first rate-limiting step in KP.2 IDO1 is widely ex-
pressed in various organs and cells while TDO is constitutively ex-
acid (3-HAA) can reduce proliferation and increase preferential apoptosis
of both T helper 1 (TH1) lymphocytes and natural killer (NK) cells.10,11 In
addition, QA, 3-HK and 3-HAA are neurotoxic which is related to the
death and/or apoptosis of neuronal.8,12 The dysregulation of KP is strongly
associated with neurological diseases such as Alzheimer’s disease (AD) and
Huntington’s disease.2,13–16 Hence, IDO1 and TDO have been regarded as
important targets for the treatment of cancer and AD.17
pressed in the liver and brain1,3
.
IDO1 and/or TDO are overactivated or overexpressed in many human
cancers, which is associated with poor patient outcomes.4,5 IDO1 and TDO
mediated depletion of Trp and production of kynurenine (Kyn) can pro-
vide an immunosuppressive tumor micro-environment, in which effector T
cells (Teff) and natural killer (NK) cells are suppressed, T regulatory cells
(Treg) are activated, and myeloid-derived suppressor cells (MDSCs) are
expanded.6,7 Furthermore, some KP metabolites have immunosuppressive
ablitities. For example, quinolinic acid (QA) can inhibit the responses,
proliferation and survival of Teff and promote the survival and metastasis
of tumor cells.7–9 3-Hydroxykynurenine (3-HK) and 3-hydroxyanthranilic
At present, a variety of IDO1 inhibitors including epacadostat
(INCB024360), BMS-986205 and PF-06840003 have been subjected to
clinical trials.18–20 Some TDO inhibitors including LM10, 680C91 and
NSC36398 are evaluated in animal experiments.4,21,22 Besides, several
IDO1/TDO dual inhibitors are also under clinical or preclinical studies,
such as navoximod (GDC-0919, NLG919), RG-70099 and SHR9146
(NCT03208959, HTI-1090), although the structures of RG-70099 and
SHR9146 have not been disclosed (Fig. 1).23,24 However, new and vi-
able IDO1/TDO dual inhibitor skeletons are severely lacking. Thus, it is
urgent to develop IDO1/TDO dual inhibitors.
Abbreviations: Kyn, kynurenine; KP, kynurenine pathway; Trp, L-tryptophan; NAD, nicotinamide adenine dinucleotide; IDO1, indoleamine 2,3-dioxygense1; TDO,
tryptophan 2,3-dioxygenase; QA, quinolinic acid; PA, picolinic acid; Teff, effector T cells; NK, natural killer; Treg, T regulatory cells; MDSCs, myeloid-derived
suppressor cells; AD, Alzheimer’s disease; 3-HK, 3-hydroxy kynurenine; KA, kynurenic acid; m-CPBA, meta-chloroperbenzonic acid; NMO, N-methylmorpholine-N-
oxide; NBS, N-bromosuccinimide; AIBN, azobisisobutyronitrile; r.t., room temperature; DCM, dichloromethane; DMA, N,N-dimethylacetamide; DMF, N,N-di-
methylformamide; THF, tetrahydrofuran
⁎ Corresponding author.
E-mail addresses: 1731041@tongji.edu.cn (Y. Li), 17110700084@fudan.edu.cn (S. Zhang), 1831059@tongji.edu.cn (R. Wang), 1931000@tongji.edu.cn (M. Cui),
weiliu2015@ntu.edu.cn (W. Liu), yangqing68@fudan.edu.cn (Q. Yang), kuangcx@tongji.edu.cn (C. Kuang).
https://doi.org/10.1016/j.bmcl.2020.127159
Received 16 January 2020; Received in revised form 25 March 2020; Accepted 27 March 2020
0960-894X/©2020ElsevierLtd.Allrightsreserved.
Pleasecitethisarticleas:YuanyuanLi,etal.,Bioorganic&MedicinalChemistryLetters,https://doi.org/10.1016/j.bmcl.2020.127159

Y. Li, et al.
Bioorganic&MedicinalChemistryLettersxxx(xxxx)xxxx
Fig. 1. Structures of IDO1 selective inhibitors, TDO selective inhibitors and IDO1/TDO dual inhibitors in clinical or preclinical trials.
Tryptanthrin (indolo[2,1-b]quinazoline-6,12-dione), an in-
Compound 5a-5h were synthesized by utilizing compound 4 as a
reactant, while compound 9a-9d were synthesized by the reaction of
compound 8 as a substrate (Scheme 2). Compound 4 was oxidized to
compound 5a with N-methylmorpholine-N-oxide (NMO). Compound 4
was reacted with sodium azide to introduce an azide group, which was
further reacted with propiolic acid under the catalysis of cuprous iodide
and sodium ascorbate to yield compound 5b. Compound 5c, 5e and 5g
were synthesized through the reaction of compound 4 with methyl 4-
piperidinecarboxylate, methyl 3-piperidinecarboxylate and proline
methyl ester hydrochloride, respectively, in the presence of triethyla-
mine and potassium iodide. Compound 5d and 5f were obtained by
reacting compound 4 with 4-piperidinecarboxylic acid and 3-piper-
idinecarboxylic acid, respectively, in the presence of potassium iodide.
Compound 5h was afforded by the hydrolysis of compound 5g in the
alcohol solution of sodium hydroxide. Compound 9a was synthesized
through the Heck reaction of compound 8 with ethyl acrylate in the
presence of potassium phosphate and catalyzed by palladium(Ⅱ)
acetate in N,N-dimethylacetamide (DMA). Compound 9b was obtained
through the hydrolysis of compound 9a in the ethanolic solution of
sodium hydroxide. Compound 9c was synthesized through the Miyaura
reaction34 of compound 8 with bis(pinacolato)diboron under the al-
kaline condition of potassium acetate and catalyzed by [1,1′-bis(di-
phenylphosphino)ferrocene]dichloropalladium(II) (PdCl2(dppf)) in
N,N-dimethylformamide (DMF). Compound 9c was hydrolyzed in the
aqueous solution of tetrahydrofuran (THF) under the effect of sodium
periodate and hydrochloric acid to obtain compound 9d.
dolequinazoline alkaloid, possesses a wide range of biological effects
such as antibacterial, anti-inflammatory, antileishmanial, antimalarial
and antitumor activities.25–29 However, tryptanthrin is poorly soluble in
water, which greatly affects its pesticide effect.30 In our previous stu-
dies, a series of tryptanthrin derivatives were synthesized and evaluated
for IDO1 inhibitory activity.31 Subsequently, some of these tryptanthrin
derivatives have been proven to bear TDO inhibitory activity.32 After-
wards, several novel tryptanthrin derivatives have been synthesized
and evaluated, the testing results demonstrated that some of these
tryptanthrin derivatives were IDO1/TDO dual inhibitors.33 With the
continuous interest in tryptanthrins, we designed and synthesized
twelve novel tryptanthrin derivatives and evaluated their IDO1 and
TDO inhibitory activities on enzymatic levels, IDO1 inhibitory activity
on cellular level and water solubility.
Twelve novel tryptanthrin derivatives containing aldehyde group
(5a), triazole (5b), N-benzylnaphthenate (5c, 5e, 5g), N-benzyl-
naphthenic acid (5d, 5f, 5h), cinnamic acid ester (9a), cinnamic acid
(9b), boric acid ester (9c) and boric acid (9d) were designed and syn-
thesized (Fig. 2). The syntheses of tryptanthrin derivatives were de-
scribed in Schemes 1 and 2. 5-Methylisatoic anhydride 2 or 5-bromoi-
satoic anhydride 7 were synthesized by the Baeyer-Villiger reaction of
5-methylisatin 1 or 5-bromoisatin 6 with meta-chloroperbenzonic acid
(m-CPBA), respectively. 2-Methyl-8-fluorotryptanthrin 3 or 2-bromo-8-
fluorotryptanthrin 8 were severally synthesized through the reaction of
compound 2 or 7 with 5-fluoroisatin in the presence of triethylamine. 2-
Bromomethyl-8-fluorotryptanthrin 4 was obtained by reacting com-
pound 3 with N-bromosuccinimide (NBS) and azobisisobutyronitrile
(AIBN).
Twelve tryptanthrin derivatives we synthesized were subjected to
the enzymatic IDO1 inhibition assay (Fig. S1). Under the same condi-
tions, the IC50 value of INCB024360 against IDO1 was determined to be
2

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Fig. 2. Twelve tryptanthrin derivatives designed and synthesized in this work.
0.09 μM (see Table 1), which was consistent with that in literature.35
All of the tested tryptanthrin derivatives exhibited IDO1 inhibitory
of 193- and 386-fold in TDO inhibitory potency with respect to LM10,
and the increase of 16- and 32-fold in TDO inhibitory potency with
respect to 8-fluorotryptanthrin (IC50 = 0.937 μM),32 was attributed to
the aldehyde and cinnamic acid group, respectively. Compound 5d, 5f,
5g, 5h and 9a were better TDO inhibitors than 8-fluorotryptanthrin.
The TDO inhibitory activity of compound 5b, 5c and 9d was found to
be equipotent with that of 8-fluorotryptanthrin. The TDO inhibitory
activity of compound 5e (IC50 = 2.87 μM) and 9c (IC50 = 6.02 μM)
was about 4- and 2-fold higher than that of LM10, although it was lower
than that of 8-fluorotryptanthrin. Thus, all of the twelve tryptanthrin
derivatives we synthesized were IDO1/TDO dual inhibitors.
activity. Furthermore, compound 9a (IC50
= 0.19 μM) and 9b
(IC50 = 0.12 μM) with cinnamic acid ester and cinnamic acid group,
respectively, showed much better IDO1 inhibitory activity than with 8-
fluorotryptanthrin (IC50 = 0.534 μM)31 and showed comparable po-
tency with INCB024360. The IDO1 inhibitory activity of compound 5a,
5b, 5d, 5f, 5g and 5h was similar to that of 8-fluorotryptanthrin.
Whereas compound 5c, 5e and 9d led to about 2- to 3-fold drop of
potency in the IDO1 inhibitory assays than 8-fluorotryptanthrin.
However, the IDO1 inhibitory activity shown by compound 9c
(IC50 = 13.09 μM) which contained pinacol borate group at the 2-
substituent of tryptanthrin exceeded 10 μM.
To further study the IDO1 inhibitory activity of tryptanthrin deri-
vatives, the cellular IDO1 inhibitory activity of the twelve compounds
was tested using HeLa cells (Fig. S3). Under the same conditions, the
IC50 value of INCB024360 was determined to be 0.02 μM (see Table 2),
which was consistent with that in the literature.18 The cellular in-
hibitory activity of most of the compounds (5a-5c, 5e and 9a-9d) were
better than enzymatic inhibitory activity, which is probably due to the
complexity of the enzyme.4,37,38 In particular, compound 5b, 9a and 9b
severally containing triazole, cinnamic acid ester and cinnamic acid
The twelve tryptanthrin derivatives were tested for the ability to
inhibit TDO on enzymatic levels (Fig. S2). Under the same conditions,
the IC50 value of the well-known TDO inhibitor LM10 was determined
to be 11.58 μM (see Table 1), which was consistent with the value re-
ported by Dolušić.36 All of the twelve tryptanthrin derivatives showed
TDO inhibitory activity and were superior to LM10. Particularly, in
compound 5a (IC50 = 0.06 μM) and 9b (IC50 = 0.03 μM), the increase
Scheme 1. Synthesis of 2-bromomethyl-8-fluorotryptanthrin 4 and 2-bromo-8-fluorotryptanthrin 8. Reaction conditions: (a, d) m-CPBA, DCM, 4 h, r.t.; (b, e) 5-
fluoroisatin, Et3N, CH3CN, 4 h, 85 ℃; (c) NBS, AIBN, CCl4, N2, 12 h, 80 ℃.
3

Y. Li, et al.
Bioorganic&MedicinalChemistryLettersxxx(xxxx)xxxx
Scheme 2. Synthesis of compound 5a-5h and 9a-9d. Reaction conditions: (a) 1) NMO, CH3CN, 2 h, r.t.; 2) 3 h, 85 ℃; (b) 1) NaN3, CH3COCH3, H2O, 10 h, r.t.; 2) CuI,
Na ascorbate, propiolic acid, 8 h, 100 ℃; (c, e, g) KI, Et3N, CH3CN, N-benzylnaphthenate, 4 h, r.t.; (d, f) KI, CH3CN, N-benzylnaphthenic acid, 4 h, 80 ℃; (h) NaOH,
CH3OH, H2O, 5 h, r.t.; (i) ethyl acrylate, Pd(OAc)2, K3PO4, DMA, N2, 8 h, 140 ℃; (j) NaOH, EtOH, H2O, 5 h, r.t.; (k) PdCl2(dppf), KOAc, DMF, bis(pinacolato)diboron,
N2, 18 h, 80 ℃; (l) 1)NaIO4, THF, H2O, 15 min, r.t.; 2) HCl, 5 h, r.t.
Table 1
Table 2
Enzymatic IDO1 and TDO inhibitory activities of tryptanthrin derivatives.
Cellular IDO1 inhibitory activity of tryptanthrin deri-
vatives.
Compound
Compound
IC50 (μM)
IDO1
IDO1
TDO
HeLa IC50 (μM)
5a
0.46
0.78
1.20
0.48
1.43
0.57
0.46
0.55
0.19
0.12
13.09
1.79
0.534a
0.09
NDc
0.06
1.13
0.99
0.45
2.87
0.42
0.30
0.18
0.37
0.03
6.02
1.21
0.937b
NDc
5b
5a
0.16
0.08
0.15
3.10
0.37
1.84
0.70
3.76
0.02
0.06
0.75
0.23
0.02
5c
5b
5d
5c
5e
5d
5f
5e
5g
5f
5h
5g
9a
5h
9b
9a
9c
9b
9d
9c
8-fluorotryptanthrin
INCB024360
LM10
9d
INCB024360
11.58
a
The enzymatic IDO1 inhibitory activity of 8-fluorotryptanthrin was tested
IDO1 of compound 5d, 5f and 5h was weaker than the enzymatic in-
hibitory activity. Compound 5d, 5f and 5h were all 2-N-benzyl-
naphthenic acid substituent derivatives. The cellular IDO1 inhibitory
activity of compound 5g was similar to its enzymatic inhibitory ac-
tivity.
in ref.31
b
The enzymatic TDO inhibitory activity of 8-fluorotryptanthrin was assessed
in ref.32
c
ND: not detected.
The water solubility of these tryptanthrin derivatives was tested
(Table 3). Compared with tryptanthrin (1.339 μg/mL),30 8-fluoro-
tryptanthrin (0.741 μg/mL) was a little more difficult to dissolve due to
the imputing of fluorine group. Compound 5d, 5f and 5h containing N-
naphthenic acid group showed an increase of 20-fold boost toward
water solubility than 8-fluorotryptanthrin. The water solubility of other
compounds was similar to that of 8-fluorotryptanthrin and tryptanthrin.
group displayed excellent cellular IDO1 inhibitory activity
(IC50 = 0.08, 0.02, and 0.06 μM, respectively). The cellular IDO1 in-
hibitory activity of compound 5a (IC50
= 0.16 μM) and 5c
(IC50 = 0.15 μM) was also satisfactory. Surprisingly, compound 9c
exhibited good cellular IDO1 inhibitory activity (IC50 = 0.75 μM) al-
though it bore poor enzymatic inhibitory activity. In contrast to the
compounds mentioned above, the cellular inhibitory activity against
4

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Table 3
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reprogramming with IDO1 inhibitors: turning immunologically unresponsive 'cold'
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Water solubility of tryptanthrin derivatives.
Compound
Water solubility (μg/mL)
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1.282
1.053
16.667
1.087
14.286
0.893
15.385
0.735
1.124
0.625
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IDO1 suggesting that the cinnamic acid ester and cinnamic acid group
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Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influ-
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Acknowledgments
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This work was supported by the Key Biochemical Program of
Shanghai [grant numbers 17431902200 & 18431902600]. We thank
the Center for Instrumental Analysis, Tongji University, China.
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Appendix A. Supplementary data
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.bmcl.2020.127159.
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