Synthesis and characterization of Sant-75 derivatives as Hedgehog-pathway inhibitors

Article abstract of DOI:10.3762/bjoc.8.94

Sant-75 is a newly identified potent inhibitor of the hedgehog pathway. We designed a diversity-oriented synthesis program, and synthesized a series of Sant-75 analogues, which lays the foundation for further investigation of the structure-activity relationship of this important class of hedgehog-pathway inhibitors.

Full text of DOI:10.3762/bjoc.8.94

Synthesis and characterization of Sant-75
derivatives as Hedgehog-pathway inhibitors
Chao Che1,2, Song Li1,2, Bo Yang1, Shengchang Xin1, Zhixiong Yu1,
Taofeng Shao1, Chuanye Tao1, Shuo Lin*1,3 and Zhen Yang*1,4
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 841–849.
1Laboratory of Chemical Genomics, School of Chemical Biology and
Biotechnology, Peking University Shenzhen Graduate School,
Shenzhen 518055, China, 2Shenzhen Shengjie Biotech Co., Ltd.,
Shenzhen 518055, China, 3Department of Molecular, Cell and
Developmental Biology, University of California, Los Angeles, USA
and 4Key Laboratory of Bioorganic Chemistry and Molecular
Engineering of Ministry of Education and Beijing National Laboratory
for Molecular Science (BNLMS), College of Chemistry, Peking
University, Beijing 100871, China
doi:10.3762/bjoc.8.94
Received: 27 February 2012
Accepted: 08 May 2012
Published: 06 June 2012
This article is part of the Thematic Series "Recent developments in
chemical diversity".
Guest Editor: J. A. Porco Jr.
Email:
Shuo Lin* - shuolin@ucla.edu; Zhen Yang* - zyang@pku.edu.cn
© 2012 Che et al; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
chemical diversity; diversity-oriented; hedgehog pathway; inhibitor;
Sant-75; synthesis
Abstract
Sant-75 is a newly identified potent inhibitor of the hedgehog pathway. We designed a diversity-oriented synthesis program, and
synthesized a series of Sant-75 analogues, which lays the foundation for further investigation of the structure–activity relationship
of this important class of hedgehog-pathway inhibitors.
Introduction
The Hedgehog (Hh) signaling pathway plays an essential role in the nucleus. This activation results in the expression of specific
embryonic development and adult tissue homeostasis in meta- genes that promote cell proliferation and differentiation [1,2].
zoans. The Hh ligands activate pathway signaling by binding to The role of the Hh signaling pathway in human cancers was
a 12-transmembrane protein receptor Patched (Ptch). In the first confirmed through a study of Gorlin syndrome predis-
unbound state, the Ptch receptor inhibits the activity of the posing to basal cell carcinoma, arising from autosomal domi-
downstream seven-pass transmembrane receptor Smoothened nant mutations in Ptch [3]. Indeed, aberrant Hh signaling has
(Smo). Binding of Hh ligands to Ptch leads to the alleviation of been reported in a variety of other malignancy diseases, such as
this inhibition and eventually triggers activation of the glioma small-cell lung cancer, pancreatic cancer, prostate cancer, breast
(Gli) family of transcription factors and their translocation to cancer and multiple myeloma [4-9]. Taken together, the devel-
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Beilstein J. Org. Chem. 2012, 8, 841–849.
opment of Hh pathway antagonists has thus represented an SAG is a synthetic Hh pathway agonist that directly targets Smo
attractive strategy for anticancer therapy [10,11]. Because in a manner that antagonizes cyclopamine action, and thus it
mutated Ptch or Smo proteins are mostly responsible for the may serve as an interesting scaffold for drug development
abnormal activation of Hh related to human diseases, intense [35,36]. Recently, we have identified a Smo antagonist Sant-75
efforts have been invested to identify therapeutic inhibitors through zebrafish-based screening of a SAG-derived chemical
acting on the Smo protein. Cyclopamine (Figure 1), a natural library [37]. Interestingly, this antagonist differs from agonist
alkaloid isolated from Veratrum californicum [12,13], was SAG only in the chain length of the secondary alkylamine due
disclosed as the first small molecule inhibitor of the Hh to the different conformational changes induced. This promising
pathway through direct interaction with Smo [14,15]. result prompted us to further investigate the structure–activity
Cyclopamine can effectively induce a decrease in proliferation relationships (SAR) of Sant-75. Herein we describe our efforts
and an increase of apoptosis in several murine models [16,17]. in the development of synthetic methods for the construction of
However, the clinical development of cyclopamine as a thera- a library of Sant-75.
peutic in cancer is hampered by its poor aqueous solubility (ca.
Results and Discussion
5 µg/mL) and acid lability. Subsequently, Infinity Pharmaceut-
icals developed cyclopamine-based Smo inhibitors IPI-926 Chemistry
through structural modification on the A and D rings. IPI-926 The scaffold of Sant-75 is divided into four distinct parts,
exhibited improved pharmaceutical properties as well as a namely 3-chlorobenzothiophene (motif A), a phenyl ring (motif
favorable pharmacokinetic profile, and showed complete tumor B), 4-pyridine (motif C) and N-propyl-cyclohexane-1,4-di-
regression in a Hh-dependent medulloblastoma allograft model amine (motif D) (Scheme 1). In our earlier studies, the nature of
[18,19]. IPI-926 is currently being evaluated in the phase II trial the substituents on these regions was shown to have a
of a safety and efficacy study of patients with metastatic or profound effect on the activity. Examples of substituents
locally advanced (unresectable) chondrosarcoma and myelofi- that impart favorable activity include the alkyl group in
brosis [19,20]. Vismodegib (GDC-0449) [21-24], developed by region D.
Genentech and Curis, is another Smo antagonist which is
progressing into the phase II clinical trial for the treatment of By modification of our first generation of synthetic method-
various cancers, including advanced basal cell carcinoma, and ology [38], the new general synthesis of the derivatives of
metastatic colorectal and ovarian cancers [25-27]. Recently, Sant-75 is illustrated in Scheme 1. Accordingly, Suzuki
vismodegib was approved by the U.S. FDA to treat adult coupling of 4-bromopyridine and 3-formylphenylboronic acid
patients with basal cell carcinoma. In addition, a number of afforded biaryl aldehyde 2, which was then subjected to a
man-made inhibitors with a Smo binding affinity have been reductive amination by condensation of aldehyde 2 with N-Boc-
identified and reported [2,28-34], and some of them have cyclohexane-1,4-diamine, followed by reduction with
entered phase I development.
NaBH(OAc)3 to afford secondary amine 3. Selective alkylation
of the newly generated secondary amine was achieved by treat-
ment of amine 3 with NaH, followed by reaction with an alky-
lating reagent to give amine 4 in high yield. To complete the
synthesis, amine 4 was reacted with acyl chloride in the pres-
ence of Et3N, and the formed amide was subjected to treatment
with TFA to remove the Boc group.
Substituent-modifications on the motif A
The first series of derivatives is characterized by substituent
modifications (Scheme 2, Scheme 3) and core modifications
(Scheme 4) on the motif A. With respect to the substituent
modifications, various groups, such as polar and hydrophobic
groups, were introduced to the phenyl ring in motif A.
Scheme 2 described the synthesis of derivatives 7a–l through
the reaction of compound 4 with a number of substituted acyl
chlorides 6a–l, which were prepared from the corresponding
cinnamic acids by Higa cyclization [39,40]. It is noteworthy
that some polar groups, including amino, hydroxy and sulfon-
amide, could not tolerate the conditions of Higa cyclization, and
Figure 1: Structures of Smo antagonists and agonists.
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Beilstein J. Org. Chem. 2012, 8, 841–849.
Scheme 1: General synthetic route for Sant-75. Reagents and conditions: (a) Pd(PPh3)4, PhMe, Na2CO3, H2O, 85 °C; (b) N-Boc-cyclohexane-1,4-di-
amine, THF, NaBH(OAc)3; (c) DMF, NaH, PrI, 0 °C to rt.; (d) 3-chlorobenzo[b]thiophene-2-carbonyl chloride, CH2Cl2, Et3N; (e) CH2Cl2, TFA.
Scheme 2: Substituent-modifications on the motif A. Reagents and conditions: (a) CH2Cl2, Et3N; (b) CH2Cl2, TFA.
had to be introduced through transformation reactions after the afford the expected product 7p. 7d was directly subjected to
N-acylation step.
basic hydrolysis in MeOH to yield carboxylic acid derivative
7q.
As depicted in Scheme 3, NH2-derivative 7m was prepared
from the NO2-substituted precursor 7c by the reduction of the To increase structural diversities, compound 4 was further
nitro group to an amino group using an FeCl3–Zn system [41]. reacted with various heteroaryl acids 8a–h to yield 9a–h
Subsequently, capping the amino group with a sulfonyl or (Scheme 4). The following considerations were taken for the
acetyl group led to 7n and 7o, respectively. In regard to selection of the heteroaryl acids: removal of the Cl atom (8a);
hydroxy or acid modification, the demethylation or hydrolysis replacement of the S atom with N or O atoms (8b, 8c); two
released the corresponding hydroxy group or carboxylic acid. heteroatoms in a five-membered ring (8d–f); and a 5,5-fused
Accordingly, 7e was treated with BBr3 in CH2Cl2 at −78 °C to ring heterocycle (8h), all of which will help us to more
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Beilstein J. Org. Chem. 2012, 8, 841–849.
Scheme 3: Substituent-modifications on the motif A. Reagents and conditions: (a) (i) FeCl3, Zn, H2O, DMF, 100 °C; (ii) TFA, CH2Cl2; (b) (i) MeSO2Cl,
CH2Cl2, Et3N; (ii) TFA, CH2Cl2; (c) (i) AcCl, CH2Cl2, Et3N; (ii) TFA, CH2Cl2; (d) BBr3, CH2Cl2, −78 °C; (e) KOH, MeOH, H2O.
Scheme 4: Core modification on the motif A. Reagents and conditions: (a) BOP, DIEA, DMF; (b) CH2Cl2, TFA.
distinctly study the SAR in motif A. Compounds 8a–h were Substituent-modifications on the motif B
either synthesized using reported methods [42-46] or are In the second series of novel scaffolds, structural modification
commercially available.
was focused on alternatives to the phenyl ring to improve
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Beilstein J. Org. Chem. 2012, 8, 841–849.
aqueous solubility. As illustrated in Figure 2, we replaced the able. However, application of the reaction conditions identical
phenyl ring with a variety of structurally diverse heteroaryl to those used in the synthesis of compound 2 (Scheme 1)
groups, including pyridine, pyrimidine and imidazole rings. In resulted in very low yields. After systematic optimization of the
order to investigate the effect of the N-position in the heteroaryl reaction conditions, we found that the reaction proceeded well
ring, different pyridine and pyrimidine substituents were also in 1,4-dioxane at 100 °C for 8 h with Na2CO3 as base in the
incorporated. Generally, the compounds 10a–g were synthe- presence of Pd(OAc)2 as catalyst, and PPh3 as ligand, providing
sized following the general route in Scheme 1, by using alde- the products in 73–85% yield.
hydes 11a–g as key intermediates. As described in Scheme 5,
11a–d were prepared through Pd-catalyzed Suzuki coupling of Different from the synthetic strategy of 11a–d, the pyrimidine
4-pyridylboronic acid with corresponding formyl-functional- nucleus in biaryl aldehydes 11e–f had to be constructed through
ized pyridylbromides 12a–d, which were commercially avail- condensation of a protected β-ketoaldehyde with the corres-
Figure 2: Core modification on the motif B.
Scheme 5: Synthesis of key intermediate biaryl aldehydes. Reagents and conditions: (a) Pd(OAc)2, PPh3, 1,4-dioxane, Na2CO3, 100 °C; (b) cat.
NaOMe, MeOH; then NH4Cl; (c) acetylacetaldehyde dimethyl acetal, 1,4-dioxane, reflux; (d) SeO2, 1,4-dioxane, reflux; (e) DMF-DMA, PhMe, reflux;
(f) acetamidine hydrochloride, Na, EtOH, reflux; (g) 1H-imidazole-4-carbaldehyde, DMF, CuI, Cs2CO3.
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ponding amidine. Compound 11e was synthesized from isonico- azine and homo-piperazine, were also investigated. Accord-
tinonitrile through three steps described previously. Isonicotino- ingly, a small series of Sant-75 analogues 18a–j were synthe-
nitrile was converted to isonicotinamidine hydrochloride 13 sized in a parallel fashion from the corresponding intermediates
upon reaction in MeOH in the presence of catalytic NaOMe, 19a–j. For intermediates 19a–j, different coupling reactions
followed by treatment with NH4Cl. Then, condensation of 13 were required to achieve their synthesis, depending on the type
with acetylacetaldehyde dimethyl acetal in 1,4-dioxane afforded of structure. 19a–d were prepared through Suzuki coupling as
6-methyl-2-(4-pyridinyl)pyrimidine 14 in 62% yield [47]. described above, and 19e–g were obtained in 70–85% yield by
Consequent allylic oxidation of 14 with selenium dioxide gave Ullmann coupling of 3-bromobenzaldehyde with an excess of
11e in moderate yield. Likewise, compound 11f was prepared the appropriate amines 20e–g [49]. The Buchwald coupling of
though SeO2-oxidation of 16, which was prepared by the protected 3-bromobenzaldehyde with amines 20h–j proceeded
reported method using 4-acetylpyridine as the starting material smoothly in toluene with NaOt-Bu as base by using a
[48]. 4-Acetylpyridine was converted to enaminone intermedi- Pd2(dba)3/rac-BINAP catalysis system [50].
ates 15 upon treatment with DMF-DMA in toluene under
reflux, followed by condensation cyclization with acetamidine Substituent-modifications on the motif D
to give 16. Compound 11g could be installed in single It has previously been shown that the substitution pattern on the
step by Ullmann coupling of 17 with 4-bromopyridine, in good nitrogen atom of trans-1,4-diaminocyclohexane moiety plays a
yield.
critical role in the activity of the compounds as Hedgehog-
pathway inhibitors. Therefore, the emphasis of the fourth series
of structural optimization was placed on the nitrogen atom
Substituent-modifications on the motif C
In the third round of structural modifications, chemical diver- through capping of the amino group with various acyl chlorides,
sity was explored by varying the nature of the heterocycles delivering the corresponding amides 21a–j. It should be noted
(motif C) and the position of the nitrogen atom in pyridine. As that the capping of the amino group can increase the metabolic
shown in Scheme 6, para-substituted pyridine was first replaced stability of the compounds. The R2 group in modified com-
with meta- and ortho-pyridine, and other heterocycles, pounds was extensively studied, including alkyl, cycloalkyl,
including pyrimidines and five-membered heteroaryl rings, as phenyl and heteroaryl groups, and a selection of the generated
well as nonaromatic heterocycles, such as morpholine, piper- compounds is listed in Scheme 7.
Scheme 6: Chemical modifications on the motif C. Reagents and conditions: (a) Pd(OAc)2, PPh3, 1,4-dioxane, Na2CO3, 100 °C; (b) CuI, DMF,
Cs2CO3, 120 °C; (c) (i) Pd2(dba)3, rac-BINAP, NaOt-Bu, PhMe, 100 °C; (ii) aq. HCl, THF.
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Beilstein J. Org. Chem. 2012, 8, 841–849.
Scheme 7: Chemical modifications on the motif D. Reagents and conditions: (a) R2COCl, CH2Cl2.
Conclusion
Natural Science Foundation of China (Grant No. 21102006 to
By modification of our first generation of synthesis of SAG C.C.), the Natural Science Foundation of Guangdong Province
derivatives, a second generation of the synthetic program was (Grant No. S2011010000185 to C.C.), and the Shenzhen Bio-
established, which allows structurally diverse derivatives of logical Industry Development Foundation (Grant No.
Sant-75 to be synthesized in a systematic manner. The JSA201005310118A to L.S.).
constructed library was fully characterized, which provides a
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