Cite this: Chem Soc. Rev., 2011, 40, 4279- 4285
`
`www.rsc.org/csr
`
`TUTORIAL REVIEW
`
`Boron-containino inhibitor. of ·yntheta c "f
`
`Stephen .J. Baker,*" .John \\ . Tom.,hoh and Stephen .J. 13cnk<)\ ic'
`
`R t•cL'i1'l'll I 11 Oc1t1ht'r 20 /{),
`DOI : 10. 1039/cOc, OOIJl i:
`
`lcn•ptt'tl 11th )111111111'.I' W 11
`
`fhc u'c ol horon 111 ,111.dl nwlc<.:ulc pha1111.11.:cutu.:a(, 1, 1nuc;"11w Boron·, uh1qu1tou' occ.:urrcn<.:c
`111 natur.: and the rc<.:cnl 'uccc" ofa horon1c .1c1d d1u!' (\clcadc") 111 thc chn1c h<l\c aJlc,1atcd
`111<111) concern' 1ncr 1h u'c 111 pharma<.:cull<.:ah. In addll11•n. the u111quc ph)'u.:ochcmical propcruc'
`ol horo111c acid' mai..c them .111 allractnc .1dd111on lo the 111cd1<.:1nal d1cll11\l\ toolbox
`I h1'
`1111on11I n ric11 "111 dl\<.:ll" lhe'c propcrtu;, ,111d polcnt1al bcncfih for an1onc 1ntcrc,tcd 1n lind111g
`no'cl cn1.)mc 1nluh11or'
`'\n exceptional cl;"' ol horon1c acids. the oxahoroks. \\Ill bc highlighted
`and 1hc11 propcrt1c' and u'c' \\Ill he dl\cu"cd 1n de1a1l
`I 111ally 1111.: <.:u11cnt paradigm for the
`reac.:tion of boro111~ a•1d' \\ llh cn11me nuclcoph1le' ''ill he wm111ari1cd
`
`I.
`
`Introduction
`
`,\nal}'" of succc"lul drug' and comparl\11n Ill lh<"c that
`have fa1h:d in deH;lopmenl h;nc lt:d lo 'enlln•il paper' 'uc.:h as
`I 1p1nsi..1 <'I al. 1 Gl..:c,on.' and a n:ccnl 1e\le\\ b; \\ anng,'
`dcs<.:nb1ng fa\orah(e phy\l<.:O<.:henrn:al rropCI lies
`lO 1.'Ulde
`I hc'c anah ses
`111cd1c111al chemists 111 1hc11 'trn<.:tural de"l.!n'
`e"ent1all) \lll!)!Csl that "nailer. le" hpopluh~ 111olcc.:ules \\ 111
`ha\e a greatt.:r cham:c of being su<.:cc,slul chn1cal candidate,.
`
`\frwlm1 (tit Ii'.
`" l1111cor Pl1ttr111(1«'111tutl1 Im
`/11]11 I
`l'alo , tlw. ( 11 <J./ 111.I. l 'i t I ·111wl .1h<tk<"r ,, 1111""" ·""11
`I 6511 5./.1 'Mii /cl ~ I 650 i./J
`\./I
`I"'
`"flit' 1'1·1111.ll'lw111111 Sill/< ( 1111·n 1111, /(}./ C'1<"111i1111 IJ111/d111~
`l 1111·c1111r /'(Irk I' I /f>Sll' l \' I
`( '1c1111111 r
`/J1•11t111111<·111
`.. /8/./865 ' 11'1
`l ·11111i/ 111·1//1111111<1/11. ta1
`/ti ~I 81.f 86\ <JillS
`l'u11111h1111111\11111l1111c11it1 , .//./ ftart1A IJ111/d1111•
`/'111
`( lu 111111n /)<'/ltlr/lllc Ill l 1111111111 f'aiA I' I /6\11' ( \ I
`I ·111(/il 11h/ <1 />11111111. I 11\
`I ~/.I Sf>5 1971
`I, I +I 8/.1 865 2881
`t P.11 t of the themed tSMtc on ,111.111 mokc.:u(c, 111 hu•lng)
`
`thc'e rule,, hut "'
`there arc c\<.:cpllon' lo
`,d,1a:r,,
`h
`dcmo11'lraled "11h the l 1r11hl-.1 rule or fi1c mcdic.:111al chc1111st(cid:173)
`arc gcnerall) "di 'cncd h) tal-.ing note of thc'c oh,encd
`pallcrn...
`l hc ... c pallcrns suggc\l lhal the \ olumc or 1.:hcn11cal
`'pai.:c \\ 11h111 \1l11ch mcd11.:111al chen11s1s can prnct1c.:e 1' l11n11cd
`I his con,trarnt 1s typically 111 contrast w1lh the goal ol 111cd1c1nal
`chcml\l\ to improve sck'Cll\lty l<1".1rd' 1hc1r thcrapculit l.1rncl
`.1nd 11111111111/c o!l~Wrgel i\Cll\lty. \\ h1ch the) ,lclllC\C b) .tdd1ng
`...uh ... tilution' to in<.:rca'c polcnq. usually resulting 1n h11gcr.
`mo1e hpopluhc mok..:ulc' So ho\\ c1n ,1 mcd11:1nal chcnust he
`.11n111 cllic1cnt yet increase molcculat di\c.:r,lly'' One 'ulu111111 IS
`to 1nlrodu1.:c nc\\ atoms 11110 drug nwlecuh:s that p10\lde a
`lunc11on.d role not offered h) othc1 atoms One such .1to111 that
`can fulfill the role~ of C\pand1ng molecular cl1vcr,11; and
`(HO\ 1d111g add111onal funct1onahl) " hornn
`Boron contains an cmpl) p-orb11.d \\ h1ch mai..c, 11 ;1 'llong
`clcctn1phdc and ii Le\\" acid It can rcadil) form dati\e bonds
`\\llh nu<.:lcorl11lc, and
`111 do111g
`s11
`tr.1m.form ...
`Imm an
`uncharged. trigonal-pla nar 'truclurc ( hg. I J to an an1on1c,
`lctrahcdra( structure. rim lcalllrc allcm.., It to for111 dall\C
`
`S tephen J . Bal-.cr
`
`Tl11s JOur11.il 1s
`
`lhe Roy.ii Soc1l'Yof Chem
`
`S tt (Jhcn .I. Bcnl-.01 ic
`
`Chem. Soc. Rev. 2011, 40, 4279 4285 I 4279
`
`EXHIBIT NO. x__
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1059 - Page 1 of 7
`
`

`
`Trigonal Planar
`
`Tetrahedral
`
`I ii(. I Ncu11al.111gonal-planar born111c acid lnnm d<111vc boncb \\1 lh
`nudcophilc' lo gi:111:1,11c an an10111c. 1c11 ahcdral '11 ucturc
`
`bnntb lldlh nuck:oph1les 111 e111ymc ac111c Siles pro11<l111g
`addi11nnal brnd111g allinll) These dallve bonds can provide
`gr..:ater slab1h1v llrnn the non-covaknt. hyd rophobic 1111cr(cid:173)
`a<:11nn' l)pic,d of most phar111accu11cab. yc1 they .ire .tlso
`rcl'cr\lblc. unhJ..c the covali.:111 bonds generated by su1c1de
`1nh1b11ors
`rhc allract11 c features offered by boron hal'I: not
`gon..: unnotu.:ed by the pharmaceutical industry and the us;; ol
`boron 1n pharmaccu11cals has been expand111g. with 0111:
`boro11-conlm111ng compou nd on the 1m1rkc1. Vclcadc". and
`se1eral 111 clinical triab. wh ich have h.:en rc1 icwcd elsewhere 4 1
`'
`hen so. b~-c:ause there arc very few J..11011 n natural products
`con1a1111ng boron and very h ttlc experience 111 developing
`horon-conla1111ng lhcrapeullcs.·1 there arc cont111u1ng concerns
`01er lls ch.:m1stry. pharmacology. and toxicology 1 ·onunatcly.
`these eoncl!rns arc bl!1ng dispelled as more horon-contammg
`compounds makl: their way through cl11m:al tnals.
`
`2. Boron in nature
`
`Boron commonly e.\1sts in nature as hone acid and l 'i an
`l!"en11al plant nutrient
`It is found 1n food such as f'rulls.
`vegl!tables and nuts. <llld we consume 3 7 mg o f boron daily 111
`our dll!l Wnh a plen11ful supply or boron a1·;11lablc to cells. 11\
`nut ' urpnS111g that natural products con ta1111ng boron and
`runcllonal roles for boron arc currently hc111g discovered.
`lhesc d1sco1c11cs arc recent so 11's hJ..cl) that m<.ny more roles
`for boron n:ma111 lo he uncovered f he firs t natural product
`found to contain horon was horo111yc1n. a polyether macro(cid:173)
`litk an11h1011c active against Gram-pos111ve bacu:na (l'ig. 2)
`r he macrolide li;1s a l11gh aflinity for bone acid 111 11s hydrated
`fo1111 Borom yc1 n
`targets
`the C) toplasmic membrane or
`(,ram-posill\e bacteria and C:aUSC'> a release Oi' p0 las'>illl11
`.,
`ions' Recently. boromycin was sho11n to hlllc an u -lll V
`ac1111ty
`
`Me
`
`0
`
`) "~
`o? 00°)
`Mel .... I .s:
`Mc
`t--o o ··-o
`6
`0
`
`Me
`
`0
`
`OH
`
`0
`Mc·
`·OH
`o.s 0
`HO OH
`
`Autolnducer-2
`Al-2
`
`l·ii:. 2 N;11u1.tl products con1.1111111g boron Borom)C111 .• 111 <1nt1b101u.:
`agarnsl C.rnm po~lll\C: h;.tclc11a and Al~2. a hactcnal automduccr
`111vuhcd 111 quorum scnsmg
`
`Another horon·conl;1111111g natural product w;" reported 1n
`2002 11hen boron'"" lound to he part or the natural product
`1nvohcd 111 quorum sensing."' Quor um sensing 1s a bacterial
`intcrccllular co111111u111c:111on procl!ss that coordinates gene
`c:--pre,s1on aero" cell'
`lo 1111t1all.: c1 cnts
`'uch as h10-
`lum1nescence. b10li1111
`l'o1 ma11011. pmduc110n ot
`\1rulcnce
`!'actors. <'/<
`I h1' c.:ros' tall.. oc,ur' 1d1cn b<tl'lcna rclea-,e
`molecuh:s. called auto111ducers. into 1hc1r cn11ro11men1
`l"hl!
`boron containing auto111duc:er /\I 2. a hyd1 atcd hone acid
`complc;\ 1111h a
`ll'lrahydrox) d1h}drolura11 (I 1g 2). 1\as
`1de1111ficd "'a hgand 111 an X rav structure of the aulo'>ensor
`protein I uxP 111 Regula lion of quorum sem1ng as an approach
`to an111111c:rob1al ther.qi\ 11as the su bject of a ree.:111 n;\1Cw 11
`OutS1dc ol natu1 al products. the lu ncllonal rok of boron 111
`plants '"" becom..: more understood 111 recent yea rs with
`research f'ocu'>c.:d on obser~1ng phe1101yp1c: clrnngc.:s 111 response
`to boron dclic1c.:nC\
`I l11s has rc1calc.:d that boron in the cl!ll
`wall acts lo hind polvsacchande'> Thac I'> also c11dencc for
`boron
`111
`the.: maintenance or plasma mcmbran..:s and
`metabolic pathways (1c11ewcd Ill rel 12)
`f hc.: mechanism or
`action ol boron 1n thl!se proccs..es rema111s unJ..1101\n. how ever.
`under the C{llld111ons of boron ckpn1at1on. 1t has been
`ri:ported that reac111·c t>\ygen spec1i:s accumulate, lcad111g to
`0\1da111c damage 1 I hl! role of boron 111 an1111als and plants
`has hccn rc.:e.:nll y re11e11 cd 14
`
`3. Boron in th crn 1lcu1ic~
`Bone acid has a k:thal dose ( I n,,,) s11111lar 10 regu la r la hie salt.
`thcrelore boron'' not an 1ntn11s1call) 1ox1c atom Recog111s1ng
`boron\ pntc.:nllal
`thl!rapc.:ullc 111de\.
`the use
`\>f boron
`111
`thcrnpcu11cs has 111cr1.\l'>cd 111 r~'\:c.:111 year,. I his cxpandl!d use of
`boron co111c1dcs 111th the C.:\panS1\lll of organoboron chc1111stry
`the Su1uk1
`that occurred ovc1 the last decade. for c:--ampk
`M1yaurn cross-coupling (n:f 15. rc.:~1e11cd 111 rel 16 and 17).
`Boronic acids ha1c.: been usl!d as cll!ctrophiles l<11gc.:11ng
`ac111·e \Ile residues of 1 a nous cn1ymes 111dud111g the.: prtitcasomc
`arg111ase. 1" s.:nne proleasl!s
`(1nclud1ng
`(hy Vdcade '' ). "
`P-lactama..c. '" hepatllis C 11rus (I ICV) protcasc.'1and 1hrrnnh111),"
`and others ( I 1g 1)' '" Boron hc.:tc.:rocycles hail! abo been
`studied 1nclud1ng d1.uahorn1c.:s." 11 h1ch 111h1b11 the enzyme
`!'atty acid h10s)nthe'" I (I /\131) through formatwn of an
`.tdduu 11 11h the colac:tor 111cot1nam1de ade111m: d111ucleo11de
`(N/\D). although a l lhl! 111111.· of the 011~·1nal r.:search, the
`'lruclure acl111l)
`rela1wnsl11p
`target 11as unkno11 n and
`studies wc.:rc performed 1n lhe abscncl! of this knowledge.:.
`More <:{>mprd1e11S1\C.: rc.:11c11s of boron 1nh1h1tor' have bcl!n
`puhll'dted 4 '' ''·'''
`
`4. Oxaborolcs. c hc rnis tr~ and mechanism
`
`rhe s11nplcs1o:-.aborolc11as hrsl synthesized and charncle111ed
`b) I msscll '11 and 11as fou nd to possess a l11gh hydroly11c
`stah1hly ' 1 111.,l t>rll<lll~. l1ttk attenuon h;1s been paid 10 lh1.,
`remarJ..abk .:la\\ ol bQron1c arnl\ 1~ as c11dcnccd by the fact
`that almost half 1>f the pubhc;it1ons and patent\ mcnt1on111g
`f h" Ile\\ -found
`O\aborolc ha\C b.:.:n pubhsh.:d SlllC:e 20()5
`111tcres1 1s likcl) the rc-.ult ol the e).CCpl1onal 'ugar b1nd1ng
`prop.:1t1c.:s of o\ah\>rolc unda phy~1olog1cal cond1t1ons as
`
`'1280 I Chem. Soc. Rev., 2011, 40, 4279 4285
`
`lh1s iourn.il is The Royal Society of Chenmtry 2011
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1059 - Page 2 of 7
`
`

`
`Proteasome Inhibitor
`
`Fotty acid biosynthtsls Inhibitor
`
`Arglnaso Inhibitor
`
`Sor1no protease Inhibitors·
`
`HCV NS3 Inhibitor
`
`COOH
`
`Thrombin lnh1brtor
`
`g.Lactomaso Inhibitor
`rcCX>tt
`0
`, ) H
`
`.. ,. ·lrr r N
`
`S
`
`OMO 8,0-
`
`.o t2 { - "
`B,
`"
`
`o· ¢
`
`C'>
`. the ltr't I DA .1pprmcd horon..:ontar111ng thc1apcut1c
`
`I ij.:. 1 I \;ttnplc' t>I h<>ron-n1r11;11n1ng th<·1.q>ctrl1<,. 1ndudtrtg \ <'k,1dc
`
`reported h) 1 lall 1•1 al"" In add1tt011 . 1".ahornli:' h;l\e
`ro.:centh bci.:n de\clupe<l a' cltntc<tl candidate,_ 1ndud1ng
`thi: fun~al 111lcc11011 on~dllllll}l:O\ls'' and
`for
`.\' 'l(,90
`\ '\J'l7'lX for thi: autormmune d1,ea'c P'Ona"' (I II'
`I)
`t\ ?690 l.trgi:t' I ung;tl li:uc.:\ I t R' \ '' ntheta'i.: (I i:u RS)
`and \ '
`'l7?1\ targe1' thi.: human pho,phrnhc,ter,l\e I ( P l>!
`I)
`·1111, re\le\\ 1\lll loi:u' 011
`\ '2690 and the 111cd1a111\111 of
`aclron ol the ox,1howlc aga111,t I .cu RC.,
`I he phystt:.tl prnpclllc' ol 0\,1 ho1 ok' dlllc1 I wm '1111plt:
`aryl bornn1<: at:1d' 111;11nl\ 111 their p1'
`S1111:c boron ha' an
`empt) p-01 b11al. clc1:tron "rthdraw111g and 111duc111r !!lllllJb do
`not havi.: such " gre.11 1110m:nce on the p1', "' the\ \\11tdd on
`the clcctrn111c' of a lull p-01 b1tal ol
`111 trngcn
`I hn1c\er
`e)cli11ng the boron 11110 .111 o\aborolc nng reduce' thl' pf..,
`by I ., pf.. 111111\ (I 1g. 5) 1111'" hehe1cd to he due to thi: nil!!
`strain geni.:r.tted l>j .1 fi1i:· mi:111hi:n:<l O\<tborolc 1111g 11hen thi:
`hornn atom 1' 1n
`thi: nct•tral , tngonal·pl.111.ir form
`I h<'
`noron O\~gen hond '' 'honer than a c.1rhon carhon hond
`and thl\I\ the 'ouri:i:orr111g,1ra111 'Th1,,tra1111' rcltc,i:d \\ht.:n
`the horon atom hc.:omi:' h)dro\}latcd to lorm the ni:g.111\eh
`
`NC
`
`llN26!l0
`
`I ii.:. 4
`
`Oil
`(,"' B
`l!..
`0
`
`pKn 7 8
`
`HO OH
`fl
`0
`
`Oil
`B Cl+I
`
`pKa 9
`
`Oil
`Alkyl B OH
`
`pKa<l 11
`
`HO 011
`fl
`Alkyl Oil
`
`pA 0 ot t>\ithorulc co111p.11.·d 10 .110111.111.: .ind .tl1ph.1ti. boruntc
`
`t tj.:. 5
`.1c1d·
`
`d1argcd. tetrahedral species. lhu' reducing the bond ,tnJ!lc
`from 120 to I 09 . f ht! OV<!rall effcct i-. a lo\\et1ng or the pf..
`f1 om
`- 9 for the com:,pond111g phen) I horon1c .1c1d
`to
`apprn,i111a1cly phys1olog1cal pl I. 'The horon 111 oxahorolc' \\tll
`theri:l'ore
`t.:\l\t
`111 equ1lthrium hct\\Ct.:11 1h neutral acid
`(non-hydro\ylatc<l) and charged hase (h)dro\)lated) lorms
`\\tlh an approx1 matcl) i.:qual populallon or h1llh at ph)sto(cid:173)
`log1c.d pl I In contrast. the correspond1n).! phenyl horon1t acid
`"di he mostly 111 Its trigonal plan;1r (non h\dro\:ylatedJ form
`\\tt h onl) -1% 111 ih lctrahi.:dral lorm
`I ht.: \ ludy of aryl-horon1c acids. such ;1s phen)I hommc
`acid. ri.:vcrsthly b111d111g d1ols has hccn stud1cd
`lrn over
`50 \car' \\1th th.: first r.:port h) I orand and I d\\ar<b.' Sincc
`thcn thi:\ have been widely u'ed asca1hohyd1.1te sensors '' "'J"
`I ,trh phvstcal ,tu<lics or these ri:act1ons found that h11ror11c
`c .1c1 fo rma tion \1a' fa\ored al high pl I
`Jt JJ "here the
`predominant (hy a factor of ,1t lca't 10
`IOJ) ktnt.:ttcall}
`J ·r Jrn,, tt ha' hecn
`1eact1\c species \Ii.IS the horona tc anion J
`t1.1d1 tionally
`thought
`that adduct
`for111at1011 procci:ded
`through the borona tc anion al1111ht c\ch1'11i:ly JJ l lo11e1er. a
`nc\1 consi.:nsus has cmcrg.:d rrom mori.: recent stud1i:s that
`demonstrate tha t th.: neutral. lngonal planar horomc acid
`'pecies i' the reactrH: species 111 ,0Jut1on. ·~ SI I hcrcforc. "hen
`the llC\\ paradigm IS C011stdcr.:d \\ ith1n the .:onlC\l or adduct
`formallon at physwlog1cally relc\ant pl I, the 1111phca11on "
`that O\abo111lcs c;1n more ri:adil) form dall\c bond' than can
`the corre,ponthng phenyl horomc acids
`\ N'l690 \\;1s the result ol a 111ed1c1nal chellll\llY prngrnms~
`111th the obJt.:Cll\C to dcvckip a \lll;tll. \later 'oluhlc an11 r11ngal
`agent that could pi.:nctratc human finµc1
`.ind toe· natl plate' Ill
`treat onychomycos1' holh 111tl11n the nail plate .ind 111 the
`underh 1ng nail bed Observed s11 ucture acll\ it; relatwnship'>
`(!:-i.\R) were 1cry rc~.incted allo111ng onh 'mall halogen
`'uhstttuenh on thi.: 5-postllon \\hilc all other 'uh,tllut.:nh
`g1call} reduced actm ly rl1c anttfungal acll\ll) ol \ ' ~690
`i' broad.
`tarci.:11ng dcrnliltolngy pathogen'
`I rn lwf'/1111>11
`mhmm and f'nd111phyto11 1111"11tai:mp/11·t•" a' \\Cll ,1, ri:,p1ra (cid:173)
`to1) and 111\astvc pathogcns 111clud1ng ( a11d1tla 11/1>1<1111.1,
`..l1f'ag1//r11 /111111gat11.1 ,1n<l Cnpt1>1t11'1'111111•0/om111111 (I .1hlc I)
`l hi:!\' 'l(l90 program \las conducted" tthout kmmlcdgc of
`thi: tarl'ct. l.euRS The pro~r.1111 u'ed .t pure!) phcnntyp1~·
`
`1111\ JOUrnal I
`
`!he Roy,11 So
`
`ty of Ch m1my 201'
`
`Chem. Soc. Rev., 2011 40, 4279 4285
`
`4281
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1059 - Page 3 of 7
`
`

`
`\,lllllllllll11 lnhih1lOf} Conccnlratmn (\I IC. pg mL I) or O\ilhorolc' ag<111bl Clllllll1011 fungal P•llhogcm •. Struclllll." .ICll\'lt) rcl.1t1onsh1p'
`I :ihlc I
`'h"'" the 5-nuorohc111oxaborolc as the most acll\c ' ·
`
`RI
`
`-1 I
`'\.I
`6-1
`7-1
`5-CI
`'\ \,k
`'\ (.I •
`'(''\J
`5-0\k
`
`I rubmm
`
`I
`
`lll<'llllll!l'Ophll!'.\
`
`16
`I
`16
`16
`I
`8
`8
`16
`64
`
`16
`I
`\?
`16
`2
`4
`8
`16
`32
`
`c "'""""'
`
`(>.I
`0.5
`16
`12
`I
`2
`16
`!I
`> 64
`
`( "
`
`/l('0/01'111(111\
`
`.12
`() 25
`12
`12
`2
`x
`IC>
`x
`> 64
`
`I /111111ga111'
`p
`{) 25
`x
`-I
`I
`2
`x
`16
`> Cw
`
`appniach. ohscrvmg anttlung;il <tCll\ lly while screening for
`lack of cvtotox1c11y against mammali;m cdls. The mecha111s111
`ol actlllll was dclcrm111cd through reverse gcnctics <ind found
`lO he a tRNA syn thctasc. 5
`rhcsc enzymes an.: involved 111
`'
`protc111 b1os~ nthcs1s and arc responsible for atlach1n!! ammo
`acids to the terminus or their correspondi ng tRNA molccuk'>.
`I he am111oacyl charged tRNA products arc then used by the
`nho-.01m: a' substrates for protein synthesis. The ribosome
`matches the i:orrcspond111g tRNA 10 the mRNA '-Cqucncc.
`I here arc 20 am111oacyl tRNA synthcl<l\cs (RS's). one for
`each of the ;11111110 acids It 1s 11npcral1\e that the aminoacyl
`t R A synthelasc allachcs lhc CtHn:cl amino acid to the
`1cn11111us of the correct tRNA since errors can lead w nonsense
`p1otc111-. The 11bosomc docs 1101 prool read the amino acid
`n ·r.1m thl! a1111codon or the tR NA <tnd will 111thsl!rim111at..:ly
`111\l!rl th..: ammo acid on thl! terminus of the l R ts.A o n lo the
`proh.:111 bc111g synthes11ed In o rder to ma111ta111 fldcht)'. 7 oul
`of JO ;11111:1oacyl tRNA 'yn thclase' have two doma111'. a
`'Y n1hcl1c domain and an cd1 ling domain. each \\ ith a umquc
`acun: \I ll!
`I hi.: syn thcuc acuvc Sill! charges the ammo acid
`t>nlo
`lhc
`tRNA and
`the cdit111g active site hydrolyzes
`nm-charged l RNA 's.
`rhc tR
`\ '>nthetascs hdong to one or the l\\O classes.
`Cla" I and Class 11. depending on 1heir structure Class I RS's
`am1noal!yla tl! the 2'-hydro>.;1 group of lhc ribosl! nng of the
`ti.:rmtnal adcnos1nc or tRNA whereas Class II RS\ amino(cid:173)
`ai;ylatc thl! 1' hydroxyl group. w11h 1hc e>.ccpllon of phenyl(cid:173)
`al;1111ni.: tRNJ\ synlheta..,c (PhcRSJ." fhcir central cellular
`runc11011 mark' aminoacyl tRNA synthclascs fo1 lhcrapcul1L
`purposl!' and most activity 111 this area has rc,ohcd around
`1nh1h1lors 101
`:1n11-111lcctl\e
`therapy.
`\\h1ch has h..:en
`rl!ncwcd ' "' Io da tc. only o ne an11noacyl 1R J\ synlhclase
`111h1h11or. 111up1roc111. '"" been launched onto 1hc market.
`although then.: arc sC\Cral prom1smg candidates currently 111
`d1111l!al 1na l' (I 1g. 6).
`l\lupll'oc111 1s a naturally occurring
`anl1b1ollc. ong111ally isolated from P.1t•11tlo111mras j/11on•sc<•111.
`and
`ta1 gets Grnm-pos11i1e bacteria induding me1h1c1llin(cid:173)
`rcs1'tant S11111hl'lonlcrn.1 a11rc•111 (MRSA) Mupiroc111 works
`hy 111h1b1tlll!! lhc sy ntheuc active sue o f bactl!nal isolcucvl
`tRNA synthl!tasc (Ile RS). thus slllpp111g thc cha rging o f lie to
`1RN1\ ' 111 andshutlmgdm,nproh:111synthcsis lhcsuccl!s\of
`
`OH
`J..
`HO
`I
`l
`I o
`
`H
`
`OH
`
`0
`,(
`H
`Me
`
`yf(O~OH
`0
`0
`
`Mupiroc1n
`
`'.I up1n>e111. 1hc onh 111a1lc1cd 111h1hno1 of "" :11111110<1cyl
`I ig. <>
`tRNA synihcla'c ("olcuc~I tRN \ s)nlhctasc)
`
`mup1roc111 has vahdat.:d an11noacyl l R A synthl!tascs as an
`anl1 -1111Cctl\C la rgi.:l.
`l.i.:u RS 1s rcspo11'1hlc for diargmg ll!uc111e onto tRNA 1 1 1
`(I 1g 7) ll 1s a mcmhl!r nf lhl! Class I tRNA s7nlhctascs .ind
`contains hoth "nthi.:sJS .ind i.:d1ting domain'> \\llh active '>I les
`'cparatcd b) apprn\1111a1cly. 10 A. I he ')nthctic act1v.: -.11.: ol
`l.l!uRS d1Splays l11gh sclcct1\ 1l\ for lcuc1111.: O\'l!I 17 other
`amrno arnh I l<mcver. 11 1s It.:" able 10 -.elect for leucinc over
`\:d1m: 01 1'oleuc111c and mis-111corporatcs these am1nl1 acids :11
`,1 rate l11gh cnou!!h such that nature has retained an edlllng
`doma111 lo proof read the an111w acid cha rged onlO l RNA 1 1 1
`I hl! cd11111g doma111 '"II hydroly1.: any am111o:icyl-t RNA ester
`hond th•ll flts 11110 the active s1li.: pocket This pocket has been
`clcs1gnl!d 10 e\cludc ll!uc1nc tRNA. " lrn;h 1.annot access the
`ecl111ng acuve 'ille and 1s th..:rcl'orc rclea\cd by the .:111ymc. B)
`and lie tRNJ\ 111
`l!Onlrilsl. 1111scharl!cd Val
`fits 1nlo the
`cd1lln!! ,1ct1 vc '1lC pockl.!l all0\\ 1ng for lhe1r hydrolysis. rhu'
`lhl! sy.11thi.:t1c and cd11111µ active sites work together to select for
`!l!uc111c mer the 19 o thcr amino acids and ma1nta111 lidellt\ o f
`protein 'Yllthcs1S
`'
`M1crob1olog1cal and hwchcnm:al studies on th..: mccha111Sm
`or AN.,690 shO\\ lha l tlm compound spcc11icall) targets the
`cd11111g domain of I cu RS 1
`It 1s non comp..:11t1ve "11h leuc111c
`fl is a slo"(cid:173)
`;ind J\ IP but docs rcqu1rl! tR NA for 1nh1b1t1on
`llght b1nd1ng inh1b11or and. once the LeuRS 1R N/\-1nh1b11or
`complc:>t is formed. 1t is qu ite stable with a ha ir life of O\Cr
`5 hours.
`I urthc1
`strncturi.: acll vity
`rcla11onsl11p studies
`confirmed that boron \\as csscn11al for 11s ac tivi ty as carhon
`analogs prmcd lo b.: 111:1c11vl!
`It was alsn d..:monstrnt.:d thill
`the lh.:-mcmbercd oxaborole nng was requ ired for ac11v11v
`s111ec neither the six-mcmbcrcd o.\abonn nor co1rl!spond1ng
`al!ycllc horon1c .1..:1th were .11.:tl\e.
`
`4282 I Chem Soc. Rev., 20 I I. 40, 4279 4285
`
`This JOurnal 1s The Royal 5ooety of Chemistry 20 ' 1
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1059 - Page 4 of 7
`
`

`
`NH1
`~N:rN
`. IV
`0 N N.,I
`\:-!
`~ 110 OH
`H~ 0
`
`N
`
`0 N N
`-...:.....;
`6 6H
`
`0
`
`H:r-OH
`
`ATP pp,
`
`Leucne
`
`0
`
`0
`
`0
`
`t~
`
`"'
`
`,.)Ip
`
`NH2
`~NjAN
`ff 0Nr-r
`'Cl
`
`~ HO ;o
`
`NHz
`
`,.........
`
`Leucine·IRNAlou
`
`I· ii:. 7 Rcac1ion .:.11.il)tcd '" lcun I I RN,\ "n1hc1.i'c" ii l\\O·,lcp pnx:c" I 11,1, lc11nnc rcaLl' wtth J\ IP to fo1111 an a<:ll\ .ttcd lcuq I· \\II' c'lc1
`\\llh 1hc lo" ol p)wph<"ph.11c. then .1 t1an'c'1c111tca1u111p11><:c"1cln<.:;11c' 1hc lcucuu: nntn thc 1c1111111.il adcnn"nc nf 1R1' \ 111 '"th lh< ''"' ol'
`\\,IP rhc ptodU<:l , lcuc) l·lRN \ 111 • ''then ll'<'d h) llW 1th<1'lll11C for ptolctn ')ttlhc't'
`
`Ad /'
`
`0 ,::.
`
`0
`
`tRNA
`
`l·ij!. II
`\.·Rit) <:l)'tallogr.1pll\ 'h"'" hornn 111 .1 'Ptrll .:11111plc\ Mlh
`the < 11-1hob ol the lcr llltnill .1dc111"111c ,,f 1RN\1 11
`
`'\ Ra\ cr)'lallograph1~· '1ud1c' n:,calcd thal \/\i 161JO fonm
`<I sp1rn a<l<lu1:1. 1c1r.1hcdrnl <1h.1u1 horon, "tlh lhc lcrnunal
`adcm•,inc of1hc1;t1rrc,pond111!! 1R'\ \ 111 in 1hccd11ingac11vc
`,iic 31
`( hg. 8) lhc boron ha' Jo,l 11' ongmal hydHl\)ol l'roup
`and ronncd 1wo nc'' bond' \\llh 1hc 7'- and ~' ·cl\ d101' of lhe
`nbo,e. I Im complc\ locb lhc lRi'- \ 111 lhc edlllll)! aCll\l! \lie.
`prc\cnllng II from either lc;l\1ng the eni)mc or mo\lng lo the
`'}nlhct1c acll\c '11c. \\hcrc ll \\(>uh.I he am111oanla1cd
`I h"
`adducl also hloi.:b olhi.:1 l R '\, \ ' from hmding to the cn1ymc
`1hu' rendering ii inai.:11\c
`I hi' lllHCI mode of inh1b111on ha'
`the o\ahornlc l RN.\ 1rapp111g, or OllOR r.
`been h:rmcd
`mci.:ha1w.111
`J\ 'tn!..1ng fea111n: of \1'1'690" 1ha1 ll "a 'mall mnlc1:uk.
`ha\lng a molernlar wc1L•h1 ol fll\I 152 a m .u
`lh1' " t \pK.111\
`t:\111'1dcn:d loo small to P'"'c" any s1gndica111 h1nd1ng allinll)
`and indeed. m:lll\ fiagmcnl·hascd hhrarn:' ha'c mcmhcr' \\ilh
`molecular \\c1ghi- 111 C\<:c" ol \ '-261JO. I hcrcforc. b;i'cd on
`c\pcricncc \\llh lr.1g111cnl hh1 .me' one would an11c1patc lhat
`\ '\ ?61JO could ,,11nplc man) h1nd111g sllc' \\ithoul c\JlCcling il
`lo ha\C any sign1fican1 phar111ai.:olog1Lal plllenq 1 l<mc\cr.
`a' .:an he seen \\llh ll' mci:han1sm ol a.:11crn. At'-2690 1s
`able lo react with the tc1 mi nu' of l RN \ 1 1 1 111 the cd11111g
`acll\e s11c and 111 doing so 1ni.:rea'>cs lls mokcul:11
`\\ c1gh1
`apprnx1111a1ely 170·fold (I ig. 8). Thi, adducl occup1c' 1hc
`entire tR'\ \ h1nding 'Ile and 1hc ed111ng actl\c 'ilc pod.cl.
`,1 \Cl) la1gc 1nl11hllor \\llh a \Cl) lugh allinll)
`resulting 111
`llll I .cu RS.
`
`rl1e mechamsm ofac11on of t\N'l690. and its reaction wllh
`1RN1\ 'pecirically. raises quesllons of 111d1\cn1111n;t1c rcacll\ll)
`and ,.:ic1:t1v1t) . I \en lhOll!'h these complc\e' form sJl(llll,t ·
`neou'I) 111 neutral aqueous 'olu11on, the) can e\changc rapid!)
`and h<l\C \Cr) weal.. asso<!lal1on .:onslanh In lhc '1mpk Lil'C
`of o\ahornlc and 1>-ribo'c lite A.., 1~ on 1hc order ol 4 \I
`al
`pl I 6 (I om,ho and Beni..O\IC. unpubhshcd rcsulh)
`\n
`11nporl;1nt feature 10 nolc " 1hal tlm A '\J261JO t R '\ \ 1 1 1
`.:omple\ \\as only observed 111 the cd11111g actl\C s11e and ha'
`1101 hecn oh,ened 111 the s}nthctic a<!l1vc sue This fa.:t leads"'
`to spcculalc lh•ll the complex" only accumulalcd \\1th111 the
`cd111ng a1:1hc Siie. where 1hc small hydrophobic pocket .tels lO
`,1ahdi1c and protccl 1hc .:omplc\ from h)drol)'"
`I hc'c
`complnc' hydrol)'1C rap1dl) in waler ,111d we hehc\C lhat lhc
`e1n m111111cn1al cond111on' ul lhc l euR ') ed111ng aLlt\c '11c li11111
`.1C1:e" of \\aler lO boron. 1hcreh) s1ab1h1111!! the .:omplc\ I he
`rca,on thcsc complexes an: not found else\\ here. w hc1hc1 111
`lhc s)nlhe11c acll\C sllc of l.cuRS or on some 01111.:1 lR
`\
`synthclasc m1ghl he due lO 1hcir .1ccess1hd1t) to \\<Iler and
`,uh,eque111 hydrolysis.
`The .:ur rent hypothesis for lhc chenrn:al reaction 111e.:han1,m
`folio'" (hg 9)
`In solu11on al ph)S1olog1cal pl I J\ ' '690
`e\isis in an .1c1d hasc equihbnum
`rapid!) 1111crcoll\crl1ng
`hclwccn ih .11110111c. h)dHn)l;11ed lelrahcdral form and lls
`neutral. 1ngonal-planar form . When lhc laucr form "held 111
`close enough pro\1m1ty 10 1hc n.1-dtcm or 1he 1 RNA one ol the
`nbose hvd10\VI groups can add lo the empt) p-orh11:d to ghc
`flu, step h hkch IO be
`the fir'l 1n1crmcd1a1c horale cstc1
`r.1p1dl) rc,cr,ihlc The ne.\I slcp could go one orihc two \\a)'
`chn11nal1on add111c1n or stil1,1i1u1ion.
`In
`lhc climina11un
`addi11011 p;llh"a). lhl! hornn h:dn"}I group 1~ 10,1 "' w;llcr
`
`This JOIJrlla l IS
`
`lhe Royal Soc Ply or Che rn1rny 20 11
`
`Chem Soc. Rev., 2011, 40, 4279 4285 I 4283
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1059 - Page 5 of 7
`
`

`
`g" 1ng a lngonal planar borate nbosc ester. which c•in the n
`cvch1.e through the second hydroxyl group of 1he 0.1-diol
`lo re,tdl 111 the sp1ro product In the sub, t1lul1 o n palh Wa).
`the second h ydroxyl group of the ci.1-diol subs titutes the
`boron lndrox' I )!roup lo result d irectly 1n the sp1ro product
`a nd wate1
`
`5.
`
`umm aq
`
`In summar~. lhc 111corpora11on of horon 1nw small molecules
`offers a nc"
`tool to the medicinal chcmist"s toolkll for
`acct:ss111g moh.:cular dl\t:rs1ty Boron 1s an t:ssen t1<il plant
`nu1ric111
`.111d " commonly found 111 naturt: as hone acid
`Reccnl d1scovcncs of horon-conla1n1ng natural produch and
`funcuon.ll rnlcs for horon 1n biology coupled 111th se,cnll
`boron conta1111ng compounds progressing th rough the chn1c
`\\Ou Id 1nd1ca tc that boron can be freely used 111 small molcculc
`therapeutics I urther morc. the phys11.:ochem1cal propert ies of
`boron. 11nh its empty p-orb11:1l, oiler new chemical d1vcrs11y to
`111ed1c111al cl11:1111stry hbranes not pro11dcd h> other commonly
`used atoms Oxahoroles ha1c hcen dcvclopcd as a n tifungal
`agents and thc1r mceha111sm o f action was discovcred to bt:
`through 1nh1h111on of lcucyl tRNA synthctasc involved 1n
`protc1n svn1hesis. Boron was round to be es,cnual to this
`meclrnn1sm o f action as 11 forms an ac11ve-s11c complc.\ with
`1111: tRNA subs1rate The rive-membered hc1erocychc n ng w<1s
`abo found to be c nl1cal to lls aCtlVlty
`fh1 s IS bcln:ved lO he
`due lo a pA,, near phys1olog1cal p l I. ria ring >tra111 . which
`allow' boron lo exist i.:q ually in neutral, lngonal-planar a nd
`negarnd; churgcd. hydroxylated.
`tetrahedral
`fo rms
`111
`h1olog1cal media
`fhus 1l 1s more capablc of rcaclrng 1\1t h
`1R A 1n 1hc ed1t1ng active site o r l .:uRS and forming a mor.:
`'.!ablc. 11gh1 h1nd1ng 111h1b11or 1han its cor responding acyclic
`boro111c acid
`l l11s m echa nism 1s likely a general 1m:cha111sm
`for boron containing compounds 1n ,ys1ems 11 here o n.: o r 1wo
`active-site nuclcophiles an: a1·ailahh.:
`lo form complcxes
`wi th boron
`
`Acknowledgements
`
`The a u tho rs would li ke lo !hank Yashet:n /.hou for provid111g
`th.: molecular model111g images.
`
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