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Mixed aryl phosphonate prodrugs of a butyrophilin ligand Benjamin J. Foust, Michael M Poe, Nicholas A. Lentini, ChiaHung Christine Hsiao, Andrew Joseph Wiemer, and David F. Wiemer ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.7b00245 • Publication Date (Web): 09 Aug 2017 Downloaded from http://pubs.acs.org on August 10, 2017

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ACS Medicinal Chemistry Letters

Mixed aryl phosphonate prodrugs of a butyrophilin ligand Benjamin J. Foust,a Michael M. Poe,b Nicholas A. Lentini,a Chia-Hung Christine Hsiao,b Andrew J. Wiemer,b,c David F. Wiemera,d* b

a

Department of Chemistry, University of Iowa, Iowa City, IA 52242-1294, USA. Department of Pharmaceutical Scic ences, University of Connecticut, Storrs, CT 06269,USA. Institute for Systems Genomics, University of Connecticut, d Storrs, CT 06269, USA. Department of Pharmacology, University of Iowa, Iowa City, IA 52242-1109, USA.

KEYWORDS: aryl phosphonates, butyrophilin, BTN3A1, ligand, phosphoantigen, prodrug

ABSTRACT: Studies of aryl phosphonate derivatives of a butyrophilin 3A1 ligand have resulted in identification of a potent stimulant of Vγ9Vδ2 T cells. This compound, a mixed ester bearing one pivaloyloxymethyl substituent and one 1naphthyl ester displayed an EC50 of 0.79 nM as a stimulant of T cell proliferation, and a 9.0 nM EC50 in an assay designed to measure interferon gamma production. In both assays, this is the most potent butyrophilin ligand prodrug yet reported, and thus it should be a valuable tool for studies of T cell function. Furthermore, mixed aryl/acyloxyalkyl esters may represent a new class of phosphonate prodrugs with high efficacy.

Proliferation of Vγ9Vδ2 T cells1 is stimulated by the presence of small organophosphorus compounds2 that bind to the signaling protein butyrophilin 3A1 (BTN3A1).3-6 The most potent natural ligand for this protein is (E)-4-hydroxy-3-methyl-but-2-enyl diphosphate (HMBPP, 1, Figure 1), which is the last intermediate in the biosynthesis of isoprenoids from 1-deoxy-D-xylulose 5phosphate that is not found naturally in the mammalian route to isoprenoids from mevalonate.7 Synthetic analogues of HMBPP that stimulate T cell proliferation also have been reported, most bearing one (or more) C-P bond(s) in place of an O-P bond (or bonds) to endow greater metabolic stability.6,8 For example, the phosphonate 2 has much greater metabolic stability than the phosphodiester 1 although it only displays cellular activity at much higher concentrations than HMBPP.9,10 A more complete understanding of butyrophilin ligands may enhance the natural anticancer activities of this unique T cell subset.11,12 Several recent studies have explored the binding of HMBPP and its biologically active analogues to BTN3A1. Originally, binding was viewed as an extracellular event.13 However more recently these small organophosphorus compounds have been shown to bind to an intracellular domain through a variety of structural, sequence swapping, and crystallographic techniques,14 as well as through isothermal titration calorimetry (ITC) and NMR studies.3 Given the growing body of evidence that

the organophosphorus ligands must cross the cell membrane to demonstrate biological activity, the high chargeto-mass ratio of HMBPP may reduce its effectiveness when extracellularly dosed. While phosphonates such as compound 2 can improve metabolic stability, to improve cell permeability we have turned to preparation of phosphonate prodrugs. The first such example, the bispivaloyloxymethyl compound 3 (POM2-C-HMBP) demonstrated an improved potency of 740-fold relative to the disodium salt 2.10 However, the question remains as to whether other prodrug forms might afford still more potent compounds. Furthermore, if prodrugs of the phosphonate ligand were to be advanced to animal studies, concerns have been expressed that pivalic acid may impact carnitine metabolism15,16 and that the serum half-lives of bisPOM prodrugs may be limited.17 For these reasons, continued investigations of other prodrug forms are justified.

Figure 1. The most potent natural ligand for BTN3A1 (1), its phosphonate analog C-HMBP (2) and its cell permeable prodrug POM2-C-HMBP (3). In theory, the simplest and most synthetically accessible prodrug form of a biologically active phospho-

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nate might be a diester of a simple alcohol such as methanol or ethanol. However, despite the discovery of organophosphorus hydrolases in some bacteria,18 there is little evidence to support metabolic cleavage of dialkyl phosphonate esters of small alcohols in mammalian systems,16 and the dimethyl esters may be particularly stable.19 However, aryl esters may have more promise as prodrugs,20-22 and both phenyl and naphthyl systems are frequent components of phosphoramidate prodrugs.16 To determine the ability of different aryl esters of phosphonate 2 to function as prodrugs, we have prepared and determined the biological activity of a small set of derivatives, and report here our findings. Synthesis of the target compounds began with conversion of dimethyl homoprenylphosphonate (4) to the phosphonic acid chloride 5 (Scheme 1).23 Given its anticipated reactivity, the acid chloride was employed in reactions with phenol or 1-naphthol after only minimal purification. Nonetheless, the expected esters 6a and 6b were obtained in good yields.

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would be expected to cross the cell membrane readily, with the methyl ester more stable to metabolic cleavage. The salt forms of the aryl esters 10a/10b would be expected to have more difficulty crossing the cell membrane due to a negative charge at physiological pH. The desired compounds were available through short synthetic sequences. Reaction of the esters 6a and 6b with pivaloyloxymethyl chloride (POMCl)24 gave the corresponding racemic mixed diesters 7a and 7b in modest yields. Installation of the allylic alcohol through selenium dioxide oxidation, followed by brief treatment with sodium borohydride to reduce any aldehyde formed, also proceeded in low yield. However, the desired products 8a and 8b were obtained in amounts sufficient for the necessary bioassays. Both compounds were obtained as racemates, which was sufficient to establish whether they demonstrate biological activity. The parent esters 6a and 6b also served as the precursors to the other pairs of target compounds. Direct selenium dioxide oxidation gave the expected allylic alcohols 9a and 9b in low yields. Fortunately treatment of the resulting esters 9a and 9b with sodium iodide in acetonitrile25 gave nearly quantitative yields of the salts 10a and 10b, with no evidence of cleavage of the aryl groups. In this way the six compounds 8a/b, 9a/b, and 10a/b were obtained for evaluation of their biological activity. Table 1. Activity for expansion of Vγ9Vδ2 T cells from human PBMC. EC50 [µM]

Scheme 1. Synthesis of homoprenylphosphonate derivatives. To explore the lability of these aryl groups in this cell system, three derivatives of both ester 6a and ester 6b were prepared to obtain compounds that might release a biologically active form of phosphonate 2 within cells. Based on our prior studies, we hypothesized that the mixed aryl/POM diesters 8a/8b would readily cross the cell membrane and undergo at least POM cleavage once inside the cell. The mixed aryl/methyl diesters 9a/9b also

Fold difference

Compound

LogP

(95% CI)

vs 2

vs 3

2 Na/Na10

-0.24

4.0

NA

NA

3 POM/POM10

3.42

0.0054

740

NA

8a Phe/POM (n=3)

3.56

0.014 (0.0040 to 0.051)

290

ND

9a Phe/Me (n=3)

2.01

33 (7.9 to 140)

ND

ND

10a Phe/Na (n=3)

1.73

0.87 (0.42 to 1.8)

4.6

ND

8b Nap/POM (n=3)

4.75

0.00079 (0.00060 to 0.0010)

5100

6.8

9b Nap/Me (n=3)

3.19

5.5 (0.029 to 1000)

ND

ND

10b Nap/Na (n=3)

2.92

0.61 (0.14 to 2.6)

6.6

ND

1

ND=not determined, NA=not applicable

Each of the six new compounds was tested first


2

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for the ability to stimulate expansion of Vγ9Vδ2 T cells (Table 1). In this assay, cells are exposed to test compounds for 72 hours to maximize cellular uptake and subsequent T cell expansion. The phenyl/methyl-protected phosphonate 9a exhibited weak activity with an EC50 in the mid micromolar range. Even weak activity of this compound was surprising, as typically dimethyl protected phosphonates are inactive.10,26 Synthetic deprotection of the methyl group gave compound 10a which showed increased cellular activity, with an EC50 value near 1 µM. Based on prior results we suspected that cell permeability would remain a barrier to the mono-salt form 10a, and therefore we assessed the phenyl/POM protected form 8a. This compound again displayed significant potency gains, with activity in the low nanomolar range. While the activity of the phenyl/POM protected compound 8a was impressive, it was slightly less potent than the bis-POM analog (3, POM2-C-HMBP), even though both compounds exhibit similar calculated LogP values and presumed cell permeability. To explore further this relationship, we hypothesized that the naphthyl group would afford further potency gains because it is more hydrophobic and, given that naphthol is more acidic than phenol by approximately a factor of 4,27 it also could serve as a better leaving group. Indeed, all three forms, the naphthyl/methyl (9b), naphthyl/salt (10b), and naphthyl/POM (8b) forms were more potent than the analogous phenyl-protected compounds. Surprisingly, the naphthyl/POM form of this compound (8b) is the most potent synthetic phosphoantigen we have identified to date, with an EC50 of 790 pM, and comparable to the natural butyrophilin ligand HMBPP (510 pM).10 Although a phenyl/POM derivative of an acyclic nucleoside phosphonate has been reported in the patent literature,28 and a phenyl/acyloxy derivative of methyl phosphonate was reported in a recent patent as a prodrug form of a carboxylic acid.29 the naphthyl/POM phosphonate protecting strategy as shown in compound 8b has not been reported prior to this work. Because it remained a possibility that the phenyl or naphthyl groups are present in cell-active forms of the parent compound, we assessed the sodium salts of these two compounds (10a and 10b) for their ability to bind to the molecular target, BTN3A1, by ITC. In these assays, no binding was observed (Figure S1). Additionally, the more potent compound 10b was tested and found to be unable to compete with HMBPP for binding to BTN3A1, even at a concentration that was 100-fold higher (Table S1). This lack of binding of protected phosphonates is consistent with our previous studies on the tris-POM versions of phosphinophosphonates, which were also unable to bind to the protein in their prodrug forms. 23 In our view, this suggests that both the phenyl and naphthyl group are susceptible to cellular hydrolysis resulting in metabolic conversion to the phosphonate dianion 2. To assess further the unique cellular potency of the naphthyl/POM compound 8b, we compared it to HMBPP (1) and POM2-C-HMBP (3), our previous mostpotent synthetic prodrug, in an ELISA assay of T cell interferon gamma production. In this assay, K562 cells were

pre-exposed for 4 hours to the test compound, washed, then co-cultured for 20 hours with T cells to stimulate cytokine production by the T cells. This exposure time is intentionally limiting to cellular uptake and meant to maximize differences between cell uptake by diffusion and by transport.30 Here (Table 2), as expected, we found that POM2-C-HMBP (3) was significantly more potent than HMBPP. Again, the naphthyl/POM compound 8b provided further gains in potency relative to POM2-CHMBP (3) and retained low nanomolar potency even when uptake times were restricted. In conclusion, these studies have shown that aryl phosphonate prodrugs of the homoprenyl phosphonate 1 effectively stimulate T cell proliferation. In the best case, compound 8b demonstrated an EC50 in the high picomolar range. Furthermore, compound 8b is ~570-fold more potent than HMBPP (1) in an assay designed to measure the ability of a compound to stimulate interferon gamma production. These results clearly encourage further studies of prodrug forms of the phosphonates that serve as butyrophilin ligands, to identify still more effective compounds. In the meantime, these new compounds represent valuable tools for studies of Vγ9Vδ2 T cell proliferation and ligand binding to the signaling protein butyrophilin 3A1 (BTN3A1). Finally, while the aryl phosphonate protecting strategy has been successfully incorporated into some phosphoramidate prodrugs, including the clinical compound Sofosbuvir,31 the potency gains on the acyloxyalkyl scaffold described herein suggest this protecting group combination may be a viable option for efficient cellular delivery of other phosphonate-containing payloads. Table 2. Activity for stimulation of purified Vγ9Vδ2 T cells to produce interferon gamma in response to K562 cells pre-loaded with test compounds. Compound

EC50 [µM] (95% CI)

HMBPP

5.1

(1)

(3.7 to 7.1)

POM/POM

0.024

(3) (n=3)

(0.019 0.031)

Nap/POM

0.0090

(8b)

(0.0075 to 0.011)

(n=3) 1

Fold difference vs 1 (HMBPP)

vs 3

NA

NA

210

NA

570

2.7

to

NA=not applicable

ASSOCIATED CONTENT Experimental procedures for the synthetic chemistry, bioassay protocols and NMR spectra. This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION


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Corresponding Author * [email protected] Author Contributions The manuscript was written through contributions of all authors and all authors have given approval to the final version of the manuscript.

Notes A.J.W. and D.F.W. own shares in Terpenoid Therapeutics, Inc. The current work did not involve the company. The other authors have no financial conflicts of interest.

ACKNOWLEDGMENTS We thank the Center for Biocatalysis and Bioprocessing for a fellowship (B. J. F.) through the Predoctoral Training Program in Biotechnology (T32 GM008365). Financial support from the NIH (R01CA186935 to AJW), and the Roy J. Carver Charitable Trust through its Research Program of Excellence (01-224 to DFW), is gratefully acknowledged.

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Table of Contents artwork here O P OH

O P

OR

O

R = CH3 R = Na R = -CH2OC(O)C(CH3)3

OH

OR

O

R = CH3 R = Na R = -CH2OC(O)C(CH3)3


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