Rational Design and Synthesis of Novel Acadesine-Like Modulators of AMPK

4 1 . I nt roduc t ion T he AMP-a c tiva te d prote in kina se , or AMPK for short, is a n e nz yme whose ide ntific a tion some 30 ye a rs a go ha s brought to inc re me nta l disc ove rie s whic h point to its e sse ntia l role in the ma inte na nc e of e ne rgy home osta sis in c e ll a nd body [1]. T he initia l disc ove ry tha t AMPK a c tivity wa s re gula te d by the AMP/AT P ra tio solve d the old c onundrum of how the c e ll se nse d a nd ma inta ine d its e ne rge tic sta tus quo a nd trigge re d a high le ve l of inte re st from the sc ie ntific c ommunity, whic h re sulte d in thousa nds of pa pe rs, publishe d ye a rly. T he se inve stiga te d the role of the AMPK pa thwa y, disc ove re d its c e ntra l role in the he a lth be ne fits of die t a nd e xe rc ise a nd sugge ste d it a s a nove l ta rge t for dise a se s ra nging from dia be te s to c e rta in c a nc e r type s a nd e ve n Alz he ime r’s dise a se . An indire c t c onfirma tion of the c e ntra l role of AMPK is its pe rva sive ne ss in the tre e of life . Homologue s of AMPK c a n be found throughout the e uka ryotic kingdom a nd its struc ture ha s re ma ine d la rge ly untouc he d throughout e volution be c a use of its ke y func tion a s a me ta bolic re gula tor of the c e ll, this role howe ve r ha s e volve d to tha t of a re gula tor of the whole -body home osta sis in more c omple x orga nisms. In ye a sts, suc h a s Sac c haromy c e s c e re v isiae the Snf1p kina se is homologue to AMPK a nd c ontrols ge ne e xpre ssion in re sponse to gluc ose de priva tion, a nd so a re the Snf1p re la te d kina se s (SnR Ks) found in pla nts whe re the y re gula te c a rbon me ta bolism a nd inhibit synthe sis of isopre noids. Also in the a nima l kingdom AMPK is highly c onse rve d from C ae norhabditis e le gans ’ a a k-2 AMPK homologue to ma mma lia n AMPK [2,4]. AMPK is a Se rine /T hre onine kina se , the se a re a va st group of e nz yme s me mbe rs of the tra nsfe ra se e nz yma tic fa mily. W he n a c tiva te d the y phosphoryla te the OH group in Se rine a nd T hre onine side c ha ins in prote ins c a using the ta rge t prote in to c ha nge its c onforma tion to a n a c tive or ina c tive sta te . T o fulfill its role a s a c e ntra l e ne rgy re gula tor for the c e ll AMPK is a c tiva te d by a de c re a se in AT P, trigge re d a s we sha ll se e by a n a lloste ric a c tiva tion from AMP, whic h se ts off its e nz yma tic a c tivity e xpre sse d by the phosphoryla tion of se ve ra l downstre a m prote ins. T his ha s the ove ra ll e ffe c t of