Synthesis of C3-Alkylated Indoles on DNA via Indolyl Alcohol

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

pubs.acs.org/OrgLett

Synthesis of C3-Alkylated Indoles on DNA via Indolyl Alcohol Formation Followed by Metal-Free Transfer Hydrogenation Pinwen Cai, Guanyu Yang, Lanzhou Zhao, Jinqiao Wan, Jin Li, and Guansai Liu* Discovery Chemistry Unit, HitGen Inc., Building 6, No. 8 Huigu 1st East Road, Tianfu International Bio-Town, Shuangliu District, Chengdu 610200, Sichuan, P. R. China

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S Supporting Information *

ABSTRACT: 3-Alkylated indole cores have been found in countless natural products and many biologically active compounds, including pharmaceuticals. In this report, a highly efficient approach to C3-alkylated indole derivatives on DNA via indolyl alcohol formation followed by metal-free transfer hydrogenation is developed. This on-DNA C3 alkylation approach is attractive because library compounds can be constructed from simple aldehydes or acid functionalized aldehydes, which are widely commercially available.

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NA-encoded chemical libraries (DECL) have increasingly become one of the most powerful hit generation methods in early drug discovery.1 The technology combines the powers of molecular biology, combinatorial chemistry, high-throughput sequencing and advanced informatics, providing access of broad chemical diversity through affinity selection. A number of novel small molecule ligands have been generated from DECL selection toward a diverse set of therapeutic targets, such as RIPK1,2 IDE,3 Wip1,4 PAD-4,5 TNKS1,6 TNF-α,7 BTK,8 PAR2,9 DDR1,10 p38MAPK,11 β2AR,12 etc. While the results from DEL selection have been impressive, substantial challenges to fully realize the potential of this technology remain. One of the most fundamental challenges is the development of new DNA compatible chemistry or utilization of known DNA compatible chemistry to construct leadlike structures.13 The needs of diverse and leadlike structures continually drive the efforts in the development of new DNA compatible reactions. The chemical space of bioactive compounds and natural products contains a large variety of heterocyclic structures. Indole is one of the most significant structural components of pharmaceuticals. Statistically, C3 of indole is the most substituted position in indole-containing drugs; 88% indolecontaining drugs were reported to be substituted at the C3 position.14 Many of them are C3-alkylated indoles (Figure 1). Although many methods have been developed for functionalization of indoles in small molecule synthesis,15 no such methods have been reported to construct such important © XXXX American Chemical Society

Figure 1. Pharmaceuticals containing C3-alkylated indoles.

structures in DECL. To this end, we report a new strategy for the synthesis of C3-alkylated indole derivatives on DNA. Building blocks underlie the chemical foundation of library diversity. The chemical diversity of one DECL strongly depends on the availability of building blocks suitable for DNA compatible reactions. We hypothesized that C3-alkylated indoles can be assembled in two steps starting from simple indoles and aldehydes16 (Figure 2), which are widely commercially available and diverse. We proposed that C3alkylated indoles can be constructed from either DNAappended indoles or DNA-appended aldehydes through indolyl alcohol formation followed by Hantzsch ester hydrogenation. This “two tagging points” approach may facilitate Received: June 20, 2019

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DOI: 10.1021/acs.orglett.9b02132 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

Table 2. Optimization of the Conditions of the Hantzsch Ester Hydrogenation

entrya 1 2d 3

Figure 2. Strategy for the synthesis of C3-alkylated indole. (A) DNA was appended on the indole ring. (B) DNA was appended on aldehydes.

1 2 3 4 5 6

67 67 67 67 200 200

buffer (mM) phosphate (83) borate (83)e borate (83)e borate (83)e borate (83)e −

d

base (mM)

3b,c (%)

− − K2CO3 (67) NaOH (67) NaOH (200) NaOH (133)

3 10 33 78 91 91

phosphate buffer (200) phosphate buffer (200)c acetate buffer (2400)e

18 90 90

All reactions were carried out with 3 (20 nmol) in THF/H2O (1/4, 50 μL). The final DNA concentration was 0.4 mM. Concentrations listed in the table were final concentrations in reaction mixtures. b Conversion determined by LC-MS. cStarting buffer stock: pH 5.5 phosphate buffer (250 mM). d3 was purified with additional spin filtration. eStarting buffer stock: pH 4.8 acetate buffer (3 M).

precipitation. In this case, use of this phosphate buffer alone produced desired products 4 in only 18% conversion yield (Table 2, entry 1), with large amounts of starting material left. If the sample of conjugate 3 was purified by spin filtration using Millipore Amicon Ultra-15 Centrifugal Filter Units, the pH of the reaction solution was kept at 5.5−6 and the conversion can reach 96% (Table 2, entry 2). Then, we realized that it would be time-consuming and cost inefficient to purify thousands of samples by spin filtration in DEL building block validation and planned to keep acidic conditions by using highly concentrated sodium acetate buffer to overwhelm the pH effects of salt residues from the last step. Finally, conjugate 4 was obtained in an excellent yield when purified 3 was treated with Hantzsch ester in acetate buffer (Table 2, entry 3). With the established conditions in hand, we investigated C3 alkylations of indoles with a wide range of aldehydes and indoles (Scheme 1). The standard conditions were found to be tolerant of many different functional groups on benzaldehydes, and various heterocyclic aldehydes, giving medium to excellent yields over two steps (Scheme 1, 7a−7o). Aliphatic aldehydes, especially with a secondary carbon (CH2) adjacent to aldehydes, gave very low yields (some examples shown in the Supporting Information). However, some cyclic aliphatic aldehydes afforded desired products with moderate to good yields (Scheme 1, 7p and 7q). The main reason for the low transformations of aliphatic aldehydes was relatively low conversions in the step of indolyl alcohol formation possibly due to low stabilities of aliphatic aldehydes under strong basic conditions. Notably, a carboxylic acid group was also tolerable in this transformation (Scheme 1, 7r and 7s), although 400 mM instead of 200 mM starting sodium hydroxide was used to overwhelm acidic effects of small molecules. This provided an optional way for DECL design by introducing another variants such as amines via amide formation. We also applied the optimal conditions to different DNA-linked indoles (Scheme 1, 7t−7z). Most of them gave excellent conversions except conjugate 7v, in which the DNA tagging point was adjacent to the reaction site. Having demonstrated the wide substrate scope study of C3 alkylation with DNA-linked indoles, we next turned to test reactions between DNA-linked aldehydes and indoles as building blocks (Table 3). It is unexpected that only 11% desired product 10 was obtained with the condition of borate buffer and sodium hydroxide at 60 °C. Instead, bis-addition

Table 1. Optimization of the Conditions of Indolyl Alcohol Formation

2 (mM)

c

a

target−binder interactions by partially avoiding steric hindrances caused by oligonucleotide tags.17 We first investigated the formation of indolyl alcohol from DNA-linked indole and benzaldehyde. Use of phosphate buffer or borate buffer alone resulted in negligible formation of desired product 3 (Table 1, entries 1 and 2). Use of borate

entrya

3b (%)

buffer (mM)

a All reactions were carried out with 1 (20 nmol) in DMSO/H2O (1/ 2, 60 μL). The final DNA concentration was 0.33 mM. Concentrations listed in the table were the final concentrations in reaction mixtures. bConversion determined by LC-MS. cParts of the target products were dehydrated in LC-MS (TM-18). which were also calculated into desired products. dStarting buffer stock: pH 5.5 phosphate buffer (250 mM). eStarting buffer stock: pH 9.4 borate buffer (250 mM).

buffer with addition of inorganic base K2CO3 provided 3 in a medium conversion (Table 1, entry 3). Encouraged by the results, we began increasing the pH by adding NaOH (Table 1, entries 4 and 5), which revealed a clear trend toward enhanced conversion under increasingly basic conditions; 91% conversion can be finally achieved using a combination of borate buffer and NaOH (Table 1, entry 5). Under this circumstance, the pH of the solution was tested at 12.8, which had already overwhelmed the buffer capacity of the borate buffer. Ultimately, use of NaOH solely instead of a combination of borate buffer and NaOH by keeping the pH around 12.8 cleanly provided 3 in 91% conversion (Table 1, entry 6). We next set out to optimize the reaction condition for the Hantzsch ester hydrogenation (Table 2). During chemistry optimization, we realized that the slightly acidic condition was critical for this transformation. Conjugate 3, which was obtained by one ethanol precipitation in the step of indolyl alcohol formation, was dissolved in pH 5.5 phosphate buffer, but unexpectedly, the pH of the solution was tested as 7−8, possibly due to salt residues in the last step after one ethanol B

DOI: 10.1021/acs.orglett.9b02132 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 1. Substrate Scope of Indolyl Alcohol Formation and Hantzsch Ester Hydrogenation

Table 3. Optimization of the Conditions of Indolyl Alcohol Formation

entrya

9 (mM)

buffer (mM)

1 2 3 4

200 200 133 133

borate (83)c borate (83)c borate (83)c −

base (mM) NaOH NaOH NaOH NaOH

(200) (200) (133) (133)

temp (°C) 60 25 25 25

10 (10a)b (%) 11 96 99 99

(89) (3.6) (0) (0)

a All reactions were carried out with 8 (20 nmol) in DMSO/H2O (1/ 2, 60 μL). The final DNA concentration was 0.33 mM. Concentrations listed in the table were final concentrations in reaction mixtures. bConversion determined by LC-MS. cStarting buffer stock: pH 9.4 borate buffer (250 mM).

compound 10a was observed as a major byproduct. We decreased the reaction temperature and the amounts of indole and bases. Quantitative desired product 10 was obtained as shown in entry 3. As discussed previously, NaOH solely was finally used instead of a combination of borate buffer and NaOH, giving the desired 10 in 99% conversion. Several acid functionalized aldehydes that were appended on DNA were screened under the above established condition followed by Hantzsch ester hydrogenation. Both aromatic and aliphatic aldehydes were shown to be tolerant and gave acceptable conversions over two steps (Scheme 2). Scheme 2. Substrate Scope of Indolyl Alcohol Formation and Hantzsch Ester Hydrogenationa

Condition of step 1: 40 μL of DNA (200 mM sodium hydroxide solution, pH 12.8, 20 nmol), 20 μL of indole (400 mM in DMSO), rt, 4 h, 1:2 DMSO/H2O. Condition of step 2: 40 μL of DNA (3 M acetate buffer, pH 4.8, 20 nmol), 10 μL of Hantzsch ester (100 mM in THF), rt, 12 h, 1:4 THF/H2O. a

Conditions of step 1: 40 μL of DNA (200 mM sodium hydroxide solution, pH 12.8, 20 nmol), 20 μL of aldehyde (600 mM in DMSO), 60 °C, 12 h, 1:2 DMSO/H2O. bConditions of step 2: 40 μL of DNA (3 M acetate buffer, pH 4.8, 20 nmol), 10 μL of Hantzsch ester (100 mM in THF), rt, 12 h, 1:4 THF/H2O. cA 400 mM sodium hydroxide solution instead of a 200 mM sodium hydroxide solution was used in step 1. a

To confirm positions of alkylation, two control experiments with 3-methylindole as a starting material were carried out under the optimal conditions (Scheme 3). No desired alkylation product was obtained. The results indirectly indicated that the alkylation happens at position 3 of indole, not on DNA backbones or on other positions of indoles. C

DOI: 10.1021/acs.orglett.9b02132 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 3. Control Experiments To Confirm Positions of Alkylation

Scheme 6. Proposed DEL Structures and Estimated Size

that C3-alkylated indoles can be constructed from either DNAappended indoles or DNA-appended aldehydes through indolyl alcohol formation followed by Hantzsch ester hydrogenation. This on-DNA C3 alkylation approach is attractive because library compounds can be constructed from simple aldehydes or bifunctional acid aldehydes, which are widely commercially available and diverse. This is an instructive example of covering leadlike substituted core structures into DNA-encoded chemical libraries to increase molecular diversity. Continued efforts in chemistry development to introduce more privileged structures in DECL will be reported in due course.

The co-injection experiment by LC-MS and HPLC of 13a from on-DNA synthesis of C3-alkylated indole and authentic sample 18 from off-DNA synthesis18 followed by the installation of DNA was carried out (Scheme 4). Two samples Scheme 4. Off-DNA Synthesis of Authentic Sample 18

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gave identical LC-MS and HPLC traces (see the detailed information in the Supporting Information). This method indirectly confirmed the characterization of desired on-DNA product 13a. To understand whether this newly developed methodology is DEL compatible, C3 alkylaton of indoles on long DNA (headpiece-primer-code 1) and its post-enzymatic ligation were evaluated (Scheme 5; see the detailed information in the

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b02132. Details of experimental procedures, copies of HPLC traces, and MS and NMR spectra (PDF)

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Scheme 5. C3 Alkylation of Indoles on Long DNA and PostEnzymatic Ligation

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Guansai Liu: 0000-0001-8925-6093 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors acknowledge Fang Jiao at HitGen Inc. for assistance on HPLC purification of DNA samples and Zhao Wang and Ping Li at HitGen Inc. for quantitative polymerase chain reaction experiments. This work was funded internally by HitGen Inc.

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Supporting Information). Indolyl alcohol formation and Hantzsch ester hydrogenation were evaluated against DNA materials with indole or benzaldehyde that were linked to 33 bp double-stranded DNA. The chemical yields were found to be consistent with yields on short DNA. No evidence of DNA decomposition was detected by LC-MS or gel electrophoresis. The product underwent efficient enzymatic ligation with a DNA tag to produce 21 and 24. The quantitative polymerase chain reaction experiment was also conducted, and no DNA damage was observed (see the Supporting Information). Under the newly developed conditions of on-DNA C3 alkylation of indoles, a DECL was proposed and the synthesis is under way (Scheme 6). Introducing three cycles of diversity brought the expected size to 30 million with commercially available building blocks as shown in Scheme 6. In summary, we report herein a highly efficient approach to constructing C3-alkylated indoles on-DNA. We demonstrated

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DOI: 10.1021/acs.orglett.9b02132 Org. Lett. XXXX, XXX, XXX−XXX

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DOI: 10.1021/acs.orglett.9b02132 Org. Lett. XXXX, XXX, XXX−XXX