Expanding Reactivity in DNA-Encoded Library Synthesis via

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Expanding Reactivity in DNA-Encoded Library Synthesis via Reversible Binding of DNA to an Inert Quaternary Ammonium Support Dillon T. Flood, Shota Asai, Xuejing Zhang, Jie Wang, Leonard Yoon, Zoe C. Adams, Blythe C. Dillingham, Brittany B. Sanchez, Julien C. Vantourout, Mark E. Flanagan, David W. Piotrowski, Paul F Richardson, Samantha A Green, Ryan A. Shenvi, Jason S. Chen, Phil S. Baran, and Philip E. Dawson J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b03774 • Publication Date (Web): 28 May 2019 Downloaded from http://pubs.acs.org on May 28, 2019

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Journal of the American Chemical Society

Expanding Reactivity in DNA-Encoded Library Synthesis via Reversible Binding of DNA to an Inert Quaternary Ammonium Support Dillon T. Flood,1⊥ Shota Asai,1⊥ Xuejing Zhang,1,2 Jie Wang,1 Leonard Yoon,1 Zoë C. Adams,1 Blythe C. Dillingham,1 Brittany B. Sanchez,§ Julien C. Vantourout,1 Mark E. Flanagan,3 David W. Piotrowski,3 Paul Richardson,4 Samantha A. Green,1 Ryan A. Shenvi,1 Jason S. Chen,§ Phil S. Baran,1* Philip E. Dawson.1 * 1Department

of Chemistry, Scripps Research, 10550 North Torrey Pines Road, La Jolla, California 92037, United States 2The Institute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China. 3Pfizer Medicinal Chemistry, Eastern Point Road, Groton, CT 06340, United States 4Pfizer Medicinal Chemistry, 10578 Science Center Drive, San Diego, CA 92121, United States §Automated Synthesis Facility, Scripps Research, 10550 North Torrey Pines Road, La Jolla, CA 92037, United States ABSTRACT: DNA Encoded Libraries have proven immensely powerful tools for lead identification. The ability to screen billions of compounds at once has spurred increasing interest in DEL development and utilization. Although DEL provides access to libraries of unprecedented size and diversity, the idiosyncratic and hydrophilic nature of the DNA tag severely limits the scope of applicable chemistries. It is known that biomacromolecules can be reversibly, non-covalently adsorbed and eluted from solid supports, and this phenomenon has been utilized to perform synthetic modification of biomolecules in a strategy we have described as reversible adsorption to solid support (RASS). Herein, we present the adaptation of RASS for a DEL setting, which allows reactions to be performed in organic solvents at near anhydrous conditions opening previously inaccessible chemical reactivities to DEL. The RASS approach enabled the rapid development of C(sp2)-C(sp3) decarboxylative cross-couplings with broad substrate scope, an electrochemical amination (the first electrochemical synthetic transformation performed in a DEL context), and improved reductive amination conditions. The utility of these reactions was demonstrated through a DEL-rehearsal in which all newly developed chemistries were orchestrated to afford a compound rich in diverse skeletal linkages. We believe that RASS will offer expedient access to new DEL reactivities, expanded chemical space, and ultimately more drug-like libraries.

Introduction Sydney Brenner and Richard Lerner’s seminal 1992 report established a profound, new type of combinatorial chemistry.1 They postulated that individual chemical transformations could be encoded in DNA, resulting in libraries of unprecedented size and chemical diversity.1 Since their proposal, many groups and pharmaceutical companies have invested heavily into DEL research and technology.2–4 Modern, industrialized DEL libraries routinely contain billions of compounds that are screened for biological activity, all at once.2–4 Although many success stories have resulted from DEL-based discovery campaigns, including multiple therapeutic candidates in clinical trials, the synthetic pathways employed during DEL construction lag severely behind the unconstrained methodologies of modern organic and medicinal chemistry.2,5–7 This glaring disparity can be attributed to the idiosyncratic reaction requirements of the encoding molecule, DNA, which manifests in three confounding

ways (Figure 1A): (1) as DNA is insoluble in most organic solvents, reactions need to be conducted in the presence of water, (2) highly diluted conditions are required (5), substituted at various positions, are also competent coupling partners affording similar yields. Finally, the scope could be further expanded to aryl bromides (which are more widely available) upon addition of 250 mM NaI forming coupled products, albeit in slightly attenuated yields. In accord with standard practice in DEL synthesis, yields are determined by integration of the total UV absorbance at 260 nm via HPLC/MS of the crude reaction mixture.13,28,29 This protocol provides an accurate measurement of relative yield on nanomole scale as DNA is the dominant chromophore.28,29 To confirm the robustness of our measurements, all of experiments using our preferred Protocol B (Figure 2B, Entry 9) were conducted in triplicate. Within the known realm of DNA-compatible chemistry, oxidative reactions are rare. This is because chemical oxidants lack chemoselectivity, indiscriminately attacking the sensitive functional groups found on the purine portion of the DNA backbone leading to degradation.30–34 Such an event in the context of DEL is deleterious and irreversible as critical encoding information can be permanently lost.31 Synthetic organic electrochemistry offers an opportunity to precisely control redox-potentials and provide superior selectivity but has never been applied in such a context.35,36 This is likely due to the charged nature of DNA that, upon exposure to an electrode surface, will irreversibly be adsorbed. RASS offers a unique opportunity to site-isolate DNA thus rendering it amenable to redox transformations accessible electrochemically that might otherwise destroy it.37 To test this hypothesis we turned to our recently reported Ni-catalyzed electrochemical aryl amination due to its highly modular nature and potential to improve upon the conditions that are currently used in analogous Pd- and Cu-based reactions (Figure 2A).38–40 Indeed, Ullmann-Buchwald-Hartwig type aminations are workhorse reactions to generate diversity in medicinal chemistry and drug discovery yet robust applications in the context of DEL are lacking.9,41 The DEL-compatible variants require exotic ligand systems, scavengers and high temperatures due to the dilute aqueous conditions employed.40 The Ni-catalyzed system was therefore investigated to probe both the DEL-compatibility of electrochemistry and to explore potential synergies with the RASS approach. As predicted, attempts to employ electrochemical amination with a traditional aqueous system led to no recoverable DNA (Figure 3B, entry 1). In striking contrast, the site-isolation garnered by the RASS approach led to

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A. On-DNA Decarboxylative sp2—sp3 Cross Coupling 3'

C C C T C A G T

3

P

O

O OH

3

(1)

N H

OH O P

N

[Ni], Reductant O Bz N NHPI RAE (100 mM) (2)

O

O

O G A G T C A

5'

RASS Reaction

OH O P

O

O

I

DNA

Bz

H N O (3)

O

B. Optimization table tbubpy

NiBr2•diglyme (mM)

Entry 1 2 3 4 5

Zn, TPPTS (40 mM), AcOH, DMA/H2O (4/1) Zn, DMA, (Representative of >100 Reactions,a see SI) N/Aa RS (300 mM), K2CO3 (300 mM), DMA/H2O (4/1), 18 h 200 DEMS (300 mM), K2CO3 (300 mM), DMA, 18 h 20 PhSiH3 (300 mM), K2CO3 (300 mM), DMA, 18 h 20 RS (300 mM), K2CO3 (300 mM), DMA, 18 h 20 RS (300 mM), K2CO3 (300 mM), DMA, 18 h 200 RS (900 mM), K2CO3 (900 mM), DMA, 18 h (Protocol A) 200 RS (900 mM), K2CO3 (900 mM), DMA, 2 x 1.5 h (Protocol B) 200 Reversed Phase and Weak Anion Exchange Resins 200 Other Strong Anion Exchange Resins 200 C. Scope of the RASS reaction

80

40

N/Aa 100 10 10

6

10

7 8 9 10 11

100 100 100 100 100

From aryl iodide

R

N

H N

DNA

H N

DNA

H N DNA

H N

O 13: 65%±11b,c

n DNA

DNA

O 11: 75%±2.6,b 80%a

DNA

O DNA O

14: 68%±3.5,b 65%a

O 12: 61%±10.6b

Me Me

Me

H N

Me H Me N DNA

H N

O 17: 69%±8.6b,c,d

O 16: 50%±12.2b,c

15: 60%a Cl HN

N

DNA

DNA O

DNA O

18: 60%±3.5b,c OBn

19: 73%±6.0b,c

H N O

DNA O

DNA

N DNA Bz N

N Boc m

DNA

H N

Boc O 23: 97%a

DNA

O o, 29: 62%a m,, 30: 53%a

DNA Br O

DNA

H N

DNA

O

H N

DNA

N H

O 33: 60%±13.1b,c

DNA O

36:

68%a

O 28: 60%a

Bz

N H

4 O

N

R

N Me N

O 37: 45%±3b,c

DNA

O 38: 43%±3b,c

N Me

Boc N

N

H N

Boc

35: 55%a

34: 82%±8.1b,c

DNA

N

H N

O

From aryl bromide

N

H N

H N

DNA

Bz

N DNA

H N

DNA

N H N

22: 72%a

O

o

C6F5 O

O 27: 60%a N

O o, 31: 60%±13.1b,c m,, 32: 82%±2.11b,c Bz N

Boc

2

O R = CH2CO2Me, 25: 49%a,c R = Ph, 26: 67%a,c

24: 70%a,d

H N

R

H N

m

o

H N

O

DNA

O 21: 73.3%±5.5b

20: 66%b,c

H H N

H N

NHBoc

Boc

Cl H N

O

H N

Boc

F

H N

82 Trace DNA up to 70%

N

H N

Boc

O n = 1, 9: 83.3%±7.2b, 78%a n = 2, 10: 80%±12.5,b 87%a

Cl O

H N

DNA

O R = CH2, 6: 62%±6.8,b,c 65%a,c R = CF2, 7: 67%±4.9b,c R = O, 8: 52%±14,b,c Br

O R = Bz, 3: 78%±3.8,b,c 84%a,c R = Boc, 4: 67%±4.6,b,c 77%a,c R = Ts, 5: 59%±7.2,b,c 56%a,c

0 100 Reactionsa

0-30 22

875 875

1000 1000

6

875

500

7 8 9

1000 1000 1000

500 500 500

5% AcOH,NMP, RT, 20 h 5% AcOH, NMP, 37º C, 20 h 5% AcOH, NMP, 37º C, 70 h

29 48 69 71

2% AcOH, NMP, 37º C, 70 h 2% AcOH, NMP, 37º C, 70 h B(OH)3 (400 mM), NMP, 60º C, 20 h B(OH)3 (400 mM), 4:1 NMP:H2O, 60º C, 20 h B(OH)3 (400 mM), 4:1 NMP:H2O, 60º C, 20 h

70 77 52

C. Scope of the RASS reaction (green) and comparison with aqueous (blue) Scope of ketone and aldehyde Pr DNA-PEG4

N H 68: 77%a b 52% Me

DNA-PEG4

N H 69: 82%±3.5a b 85%

Pr

Me

Me

DNA-PEG4

Me

DNA-PEG4 N Me H 73: 79%±2.6a 70%b

R = Me, 79: 76%±8.8,a 83%b R = tBu, 80: 59%±3.7,a 85%b

H DNA-PEG4

N H I 85: 56%±11a 39%b

81:

82:

DNA-PEG4 N

72: 16%±1.5a 75%b EtO2C DNA-PEG4

N H 78: 35%±8.5a 41%b

R = CH2, 76: 76%±5.5,a 68%b R = O, 77: 76%±6.6,a 66%b Cl

H

DNA-PEG4

N H

2

DNA-PEG4

Cl

NH

N I

27%±4a 11%b

83: 40%±14a 7%b

84: 49%±16a 82%b O

O DNA-PEG4

N H N 86: 23%±7a 10%b

N H

N H

Scope of DNA-PEG4-AA

H

N

N

73%±2a 52%b R

N H

N H

DNA-PEG4

DNA-PEG4

H

79%±3.5a 86%b

O

71:

Boc DNA-PEG4

N H

Ph

75: 72%±4a 84%b

N

DNA-PEG4

N H

DNA-PEG4

N H 74:

DNA-PEG4

70: 68%±5.3a 41%b

69%±2.2a 81%b

Me

Me O

N H

I

Me

O

R DNA-PEG4

DNA-PEG4

N H

87: 47%±9.1a 51%b

DNA-PEG4 H N

Pr Pr

N H

88: 51%±10a 70%b

N

Pr Pr

Figure 4. On-DNA Reductive Amination. (A) Reaction Scheme. (B) Optimization Table, a Reactions conducted by Pfizer and results communicated through personal communications (C) Scope Table, a On Resin, b Aqueous Reaction.


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Unlike the cross-coupling and e-amination described above, reductive amination is not strictly enabled using a RASS approach. Releasing the shackles of conventional DEL reaction development, a classical organic approach inadvertently led us to a new set of B(OH)3-mediated conditions that can function with or without RASS. As with prior examples, the reactions reported in Figure 4C were conducted in triplicate.

RASS-Enabled DEL: Toward Creating Libraries In order for new strategies to be adopted for use in DEL library construction, individual diversity generating steps must be sufficiently chemoselective and DNA recovery sufficiently efficient for at least 30% of the DNA to be recovered.31 While developing the above sp2-sp3 cross coupling, it became apparent that the reaction would result in sub-optimal DNA recovery (~20%). Fortunately, this problem was addressed by optimizing the EtOH precipitation procedure. Increasing the ratio of EtOH:elute buffer ratio from 5:1 to 10:1 resulted in satisfactory DNA recovery of ~30%. The observed low DNA recovery is likely a result of reaction workup and precipitation conditions, as opposed to actual reactivity based degradation. Fortunately, we did not observe any DNA recovery problems in any of the other reactions outlined above. To further establish compatibility with library construction, the viability of the product DNA was confirmed. After a completion of a full RASS cycle (bind, reaction, elute, EtOH precipitate) 3 was ligated to a 20mer dsDNA primer, commonly used in DEL builds. The ligation efficiency was identical to 1, DNA that had not undergone a RASS cycle (SI).14 This suggests that a DEL library member can be enzymatically encoded after an organic reaction in the RASS cycle. As a DEL library is assembled, the encoding DNA tag increases in length. The applicability of the RASS approach with an elongated molecule, was demonstrated by selectively binding and eluting a double stranded 40 base pair oligo from the same solid support used in reaction development (Srata-XA) as well as a related solid support optimized for molecules larger than 10 kDa (Srata-XAL). This larger DNA, representative of DNA

after the first encoding cycle, bound efficiently and eluted from the solid support with the same properties as the smaller DNA headpiece. To illustrate the multistep process of a DEL build, a the three reactions reported herein, were utilized sequentially (Figure 5). This three-cycle synthesis was devised using cross-coupling/deprotection, reductive amination, and finally electrochemical amination. A mock DEL build was performed using three cycles of chemistry, resulting in a skeleton, rich in linkage diversity (Figure 5). The DNA headpiece-small molecule intermediates were eluted from resin after each cycle, as would be requisite in a DEL build. Starting with 1 a decarboxylative sp2-sp3 cross coupling with Fmoc-proline was performed and the resulting product was deprotected. A reductive amination was performed on the resultant free amine, which allowed for the introduction of another aryl iodide moiety. The aryl-iodide product was then utilized in an electrochemical amination to produce the final compound 90 in 9% yield over 4 steps. This provides an example that these diversity generating chemistries can be coupled in series, through multiple RASS cycles, to yield on-DNA products that are rich in therapeutically relevant functionality.

Structural Insights In addition to facilitating reactions in neat organic solvents, the RASS-DEL approach is distinguished by a significant resistance to DNA damage. This effect that was observed during the above studies could be a result of the DNA maintaining significant double helix structure while adsorbed to the support. To investigate the conformation of the imobnilized DNA we used fluorescence microscopy to observe the dsDNA specific interaction of a DNA intercalator (Figure 6). A 40-base pair dsDNA was designed to mimic the encoding molecule in a growing DEL library. As a control, two non-hydridizing 40-mers of single stranded DNA were used. Each DNA was adsorbed to Phenomenex Strata-XAL resin, and then treated with SYBR Green which increases in fluorescence when intercalated into dsDNA. The resins were washed in acetonitrile (5x) and suspended in ethanol for microscopy. The relative fluorescence observed by

DEL Rehersal—Three RASS Cycles NH Wash Decant

Bind

De-CO2 Cross-Coupling Ni:dtbbpy (100:200 mM) RAE (100 mM) K2CO3 (900 mM) Rubin’s Silane (900 mM)

Organic Rxn

Enz. Encoding

RASS Cycle

Reductive Amination 500 mM Ketone 400 mM B(OH)3 1 M NaBH3CN 20% H2O in NMP

e-Amination Ni(bpy)3Br2 (100 mM) Amine(100 mM) Graphite Electrodes 4 mA, 3 h

Me

N

Fmoc-Deprotection 10% Piperidine in H2O 50º C, 5 h [Aqueous Reaction]

I

2

Me

Quench Wash

EtOH Ppt. Elute

HN

O

DNA

[modular] [expanded reactivity] [paralellizable]

1

De-CO2 CrossCoupling

FmocDeprotection

O HO

HN

I

O N Fmoc

ElectroChemical Amination

Reductive Amination

Me 2

O

DNA NH2 90 (9% over 4 steps)

Figure 5. DEL—Rehearsal, Graphical Workflow Representation and Synthesis of 90.



mediated reductive amination with expanded generality in both aqueous and RASS contexts was also discovered. Application of these three reactions in a DEL-rehearsal suggests that this technology is applicable to real-world library construction. Finally, structural studies have confirmed that DNA is still double-stranded while bound to the resin, a necessary proviso to protect the encoding molecule. As such, it is anticipated that this approach to DEL construction will find widespread utility.

Structural Insights

A

B

ASSOCIATED CONTENT 200 µM

C 60 Relative Frequency (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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40

****

200 µM

dsDNA ssDNA Resin

Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Detailed experimental procedures and data (PDF)

AUTHOR INFORMATION Corresponding Author *[email protected] *[email protected]

20

AUTHOR CONTRIBUTIONS ⊥These

authors contributed equally.

ACKNOWLEDGMENT

0

Relative Fluorescence Figure 6. Structural Insights. Confocal Microscopy Image of Resin with (A) Double Stranded DNA (B) Single Stranded DNA Adsorbed and Stained with SYBR Green. (C) Quantification of Resin Fluorescence.

Financial support for this work was provided by NIH (GM118176) and Pfizer. We are grateful to Dr. Dee-Hua Huang and Dr. Laura Pasternack (Scripps Research) for assistance with nuclear magnetic resonance (NMR) spectroscopy.

REFERENCES

confocal fluorescence microscopy was consistent with the dsDNA construct remaining in the duplex form (strong relative fluorescence).44–46 All experiments were normalized to the total DNA content.200 ìM As shown in Figure 6, the average fluorescence intensity of the double stranded DAN was much greater than that of the single stranded DNA and the stained resin. The increase in fluorescence between the double stranded and single stranded samples was statistically significant (p 0.05). If the DNA was predominantly denatured upon adsorbing to the resin, a reduced fluorescence output would have been observed, similar to that of the single stranded control. The observed difference in average fluorescence intensity supports the notion that DNA is double stranded while adsorbed to the resin in the presence of organic solvent.44,45

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As the use of DEL in drug discovery increases, there is a growing need to expand the tool box of organic transformations available to practitioners. In this study we have outlined how strong-anion exchange resins based on quaternary ammonium moieties (RASS) can be used to facilitaite reactions in orgainic solvents. Reactions previously outside the realm of DEL including, complex sp2-sp3 cross couplings and electrochemical aminations have been demonstrated. The realization of a B(OH)3-

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