Current Synthetic Routes to Peptidyl Mono-Fluoromethyl Ketones (Fmks) and Their Applications
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molecules Review Current Synthetic Routes to Peptidyl Mono-Fluoromethyl Ketones (FMKs) and Their Applications Carissa M. Lloyd 1, Neil Colgin 2 and Steven L. Cobb 1,* 1 Department of Chemistry, Faculty of Science, Durham University, Durham DH1 3LE, UK; [email protected] 2 Cambridge Research Biochemicals, 17-18 Belasis Court, Belasis Hall Technology Park, Billingham, Cleveland TS23 4AZ, UK; [email protected] * Correspondence: [email protected] Academic Editor: Derek J. McPhee Received: 26 October 2020; Accepted: 24 November 2020; Published: 28 November 2020 Abstract: Peptidyl mono-fluoromethyl ketones (FMKs) are a class of biologically active molecules that show potential as both protease inhibitors for the treatment of a range of diseases and as chemical probes for the interrogation of cellular processes. This review describes the current solid- and solution-phase routes employed for the synthesis of peptidyl mono-FMKs. In addition, it provides a brief overview of some of the key applications of FMKs in the fields of chemical biology and medicinal chemistry. Keywords: peptide; fluoromethyl ketone; peptide synthesis; peptide modification; fluorine; therapeutic; probe 1. Introduction Peptidyl mono-fluoromethyl ketones (FMKs) are a class of biologically active compounds that have been developed as protease inhibitors [1–5] and as chemical probes for the interrogation of cellular processes [6–8]. Peptidyl FMKs were first reported in 1985 [9] and have since gained preference in the field over the corresponding peptidyl chloromethyl ketones (CMKs), largely due to their lower reactivity towards nucleophiles. For example, peptidyl CMKs have been developed as both cysteine and serine protease inhibitors (e.g., Figure1,( 1)), but their highly reactive nature often causes issues with regards to selectivity. As such, for many peptidyl CMKs, indiscriminate binding of nonproteolytic enzymes leads to undesirable side-effects, rendering them unsuitable for in vivo applications [10]. Peptidyl FMKs are much less prone to nonspecific alkylations due to the intrinsic strength of the C-F bond making them significantly more selective [9] (Figure1,( 2), (3)). Since their discovery, the number of synthetic routes that are available to access peptidyl mono-FMKs remains rather limited, particularly when compared to those that can be used to access the corresponding peptidyl CMKs [11–13] and even peptidyl tri-fluoromethyl ketone systems (Figure1,( 4)) [14–16]. Molecules 2020, 25, 5601; doi:10.3390/molecules25235601 www.mdpi.com/journal/molecules Molecules 2020, 25, x 5601 FOR PEER REVIEW 2 of 16 Molecules 2020, 25, x FOR PEER REVIEW 2 of 16 Figure 1. Representative examples of a peptidyl chloromethyl ketone (1) [12], peptidyl fluoromethyl Figure 1.1. Representative examples of a peptidylpeptidyl chloromethyl ketone (1)[) [12],12], peptidylpeptidyl fluoromethylfluoromethyl ketones (2 [3] and 3 [2]), and a peptidyl tri-fluoromethyl ketone (4) [15]. ketones (2 [[3]3] andand 33 [[2]),2]), andand aa peptidylpeptidyl tri-fluoromethyltri-fluoromethyl ketoneketone ((44)[) [15].15]. This review provides an overview of the current state-of-the-art with regards to solid- and This review provides an overview of the currentcurrent state-of-the-artstate-of-the-art with regards to solid-solid- and solution-phase synthetic routes that can be employed for the synthesis of peptidyl mono-FMKs. In solution-phase synthetic synthetic routes routes that that can can be be employ employeded for for the the synthesis synthesis of ofpeptidyl peptidyl mono-FMKs. mono-FMKs. In addition, a brief summary of the key applications of this class of compound within the fields of Inaddition, addition, a brief a brief summary summary of ofthe the key key applications applications of of this this class class of of compound compound within within the the fields fields ofof chemical biology and medicinal chemistry is given. For a more detailed overview of FMKs within the chemical biologybiology andand medicinalmedicinal chemistrychemistry isis given.given. For a more detailed overview of FMKs within the field of medicinal chemistry, an excellent recent review of this area was published by A. Citarella and fieldfield of medicinal chemistry, anan excellentexcellent recentrecent reviewreview ofof thisthis areaarea was published by A. Citarella and N. Micale [17]. N. Micale [[17].17]. 2. Current Current Synthetic Synthetic Routes Routes to to Peptidyl Peptidyl Mono-FMKs 2. Current Synthetic Routes to Peptidyl Mono-FMKs 2.1. Solution-Phase Solution-Phase Routes Routes 2.1. Solution-Phase Routes 2.1.1. Halogen-Exchange Halogen-Exchange 2.1.1. Halogen-Exchange An earlyearly attempted attempted solution-phase solution-phase peptidyl peptidyl mono-FMK mono-FMK synthesis synthesis looked to looked use the displacementto use the An early attempted solution-phase peptidyl mono-FMK synthesis looked to use the displacementof bromide or of chloride bromide with or a chloride source of with inorganic a sour fluoridece of inorganic in a halogen-exchange fluoride in a reaction.halogen-exchange However, displacement of bromide or chloride with a source of inorganic fluoride in a halogen-exchange reaction.this approach However, did not this produce approach the desired did not FMK produce (7), but the rather, desired resulted FMK in(7 a), nonfluorinatedbut rather, resulted compound in a reaction. However, this approach did not produce the desired FMK (7), but rather, resulted in a nonfluorinated(6) along with various compound unwanted (6) along side-products with various (Scheme unwanted1)[9 ].side-products (Scheme 1) [9]. nonfluorinated compound (6) along with various unwanted side-products (Scheme 1) [9]. Scheme 1. AttemptedAttempted formation formation of of a a peptidyl peptidyl mono-fluoromethyl mono-fluoromethyl ketone ketone (FMK) (FMK) ( (77)) through through a Scheme 1. Attempted formation of a peptidyl mono-fluoromethyl ketone (FMK) (7) through a halogen-exchange reaction [[9].9]. halogen-exchange reaction [9]. Since then,then, aa successfulsuccessful halogen-exchange halogen-exchange method method has has been been developed developed and and was was reported reported by Kolb by Since then, a successful halogen-exchange method has been developed and was reported by Kolbet al. et in 1986al. in (Scheme1986 (Scheme2)[ 18]. 2) Initial [18]. isolationInitial isolation of 3-phthalimido-1-bromo-4-phenyl-2-butanone of 3-phthalimido-1-bromo-4-phenyl-2-butanone (8) from Kolb et al. in 1986 (Scheme 2) [18]. Initial isolation of 3-phthalimido-1-bromo-4-phenyl-2-butanone (N8)-phthaloyl from N-phthaloyl phenylalanine phenylalanine was achieved was through achieved generation through of thegeneration corresponding of the diazoketonecorresponding via (8) from N-phthaloyl phenylalanine was achieved through generation of the corresponding diazoketonethe acid chloride via the (not acid shown). chloride Subsequent (not shown). bromination Subsequent of bromination the diazoketone of the according diazoketone to previously according diazoketone via the acid chloride (not shown). Subsequent bromination of the diazoketone according toknown previously conditions known [19 conditions,20] led to the[19,20] formation led to the of 8 formation. Further reactionof 8. Further of 8 with reaction KF/l8-crown-6 of 8 with KF/l8- led to to previously known conditions [19,20] led to the formation of 8. Further reaction of 8 with KF/l8- crown-6FMK 9 in led a 45% to FMK yield 9 (Schemein a 45%2 ).yield Reduction (Scheme by 2). sodium Reduction borohydride by sodium enabled borohydride removal enabled of the phthaloyl removal crown-6 led to FMK 9 in a 45% yield (Scheme 2). Reduction by sodium borohydride enabled removal of the phthaloyl protecting group, however, this simultaneously reduced the ketone functionality of the phthaloyl protecting group, however, this simultaneously reduced the ketone functionality Molecules 2020, 25, 5601 3 of 16 Molecules 2020, 25, x FOR PEER REVIEW 3 of 16 protectingMolecules 2020 group,, 25, x FOR however, PEER REVIEW this simultaneously reduced the ketone functionality which had3 of to 16 be reinstalledwhich had by to Swern be reinstalled oxidation by (Swern10)[21 oxidation,22]. Vederas (10) et[21,22]. al. utilised Vederas a similar et al. utilised approach a similar for the approach synthesis 13 ofwhich afor theC-labelled had synthesis to be peptidyl reinstalled of a 13C-labelled FMK by probeSwern peptidyl which oxidation wasFMK ( used10 probe) [21,22]. to investigatewhich Vederas was used theet al. mode toutilised investigate of actiona similar ofthe theapproach mode HAV of 3C 13 enzymeforaction the [of 23synthesis the]. HAV of 3C a enzymeC-labelled [23]. peptidyl FMK probe which was used to investigate the mode of action of the HAV 3C enzyme [23]. SchemeScheme 2. 2.Formation Formation ofof FMKFMK 10 via a halogen-exchange halogen-exchange reaction reaction [18]. [18 ]. Scheme 2. Formation of FMK 10 via a halogen-exchange reaction [18]. 2.1.2.2.1.2. Synthesis Synthesis via via Direct Direct Fluorination Fluorination ofof aa DiazoDiazo Intermediate 2.1.2. Synthesis via Direct Fluorination of a Diazo Intermediate AnotherAnother initially initially unsuccessful attempt attempt involved involved the reaction the reaction of HF ofwith HF a diazomethyl with a diazomethyl ketone; ketone;a methodAnother a method analogous initially analogous unsuccessfulto that used to that attemptfor usedthe synthesisinvolved for the thof synthesise CMKsreaction (chloromethyl of HF CMKs with (chloromethyla diazomethylketones)