Synthesis and anticancer properties of new (dihydro)pyranonaphthoquinones and their epoxy analogs

ßioorganic & M edicinal Chem istry Letters 25 (20 1 5 ; 3 3 5 5 -3 3 5 8

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Bioorganic & Medicinal Chemistry Letters

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Synthesis and anticancer properties of new /£v

(dihydro)pyranonaphthoquinones and their epoxy analogs

Tuyet Anh Dang I hi , Thu Ha Vu Thi , Hoang Thi Phuong \ Thanh Ha N g u y e n C h in h Pham T h e 1,

Cuong Vu D u e ’, Yves D ep etter Tuyen Van Nguyen*1'", M atthias D’h o o g h e b

a In stitu te o f C hem istry, V ietnam A c a d em y o f Science a n d Technology, 18-H oang Quoc Viet, CauCiay, H anoi, V ietnam

bSynBioC Research Croup, D e p a rtm e n t o f S u stainable Organic C hem istry an d Technology, Faculty o f Bioscience Engineering, G hent U niversity, Coupure Links 653, B -9000

Ghent, Belgium

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ARTICLE INFO ABSTRACT

A rticle history: 1,4-Dihydroxy-2-naphthoic acid was used as a substrate for a straightforward five-step synthesis of

R eceived 7 A pril 2 0 1 5 3-substituted lH-benzo[g]isochromene-5,10-diones, with a Michael addition of N-acylmethylpyridinium

A ccen ted 2CHVU^2015 y lic le s across 2-hydroxymethyl-l,4-naphthoquinone and a subsequent acid-mediated dehydratation of

A vailable o n lin e ^ S M ay 2015 intermediate hemiacetals as the key steps. The obtained benzo[g]isochromene-5,10-diones were subse￾quently deployed for further synthetic elaboration to produce new 3,4-dihydrobenzo[g]isochromene-

~ — ---------------------------------------- 5,10-diones and (3,4-dihydro-)4a,10a-epoxybenzo[g]isochromene-5,10-diones. All compounds were

Pyranona hthoquinones screened for their cytotoxic and antimicrobial effects, revealing an interesting cytotoxic activity of

E poxides 1H-benzo[g]isochromene-5,lO-diones against different cancer cell lines.

C y to to x icity © 2015 Elsevier Ltd. All rights reserved.

N aturally occurring (dihydro)pyranonaphthoquinones can be

found in bacteria, fungi and higher plants, pointing to th eir bio￾chem ical relevance in n a tu re .' M any of these pyranonaphtho￾quinone derivatives have indeed been discovered to possess

diverse and pronounced biological activities, including antim icro￾bial, antiparasitic, antiviral and anticancer p ro p e rties/ For exam ­

ple, the dihydropyranonaphthoquinones eleutherin 1 and

psychorubrin 2 and th e p y ranonaphthoquinones pentalongin 3,

dehydroherbarin 4a and analogs 4b, 4c have been show n to exhibit

interesting antim icrobial, antiparasitic, phytotoxic and antineo￾plastic activities (Fig. I).3 Furtherm ore, pyranonaphthoquinone￾derived epoxides such as nanaom ycin antibiotics 5 (nanaom ycin

E 5a, nanaom ycin OiE 5b and nanaom ycin pE 5c), isolated from

Streptomyces rosa var. notoensis,4 and frenolicin 6, isolated from

Streptomyces f l a d i a e are know n to display biological activity

against m ycoplasm as, fungi and G ram -positive bacteria (Fig. I).1’’

These and m any o th er exam ples of bioactive synthetic and n a t￾ural pyranonaphthoquinones have clearly elicited an in terest in the

preparation of novel analogs of these classes of com pounds, and

th e synthesis of lH -benzo[g]isochrom ene-5,10-diones (also

referred to as naphtho[2,3-c]pyran-5,10-diones) has th u s been

th e subject of several studies in th e chem ical literature.

* C o rresp o n d in g a u th o r. Tel.: + 84 9 1 7 6 8 3 9 7 9 .

E -m ail address: n g v tuyen@ hotrnaiI,c.om (T. V an N g uyen).

h ttp ://d x .d a j.o rg / S 0 .1 0 1 6 /j.b m c ! ,2 0 i5.05,051

0 9 6 0 -8 9 4 X/© 2 0 1 5 E lsevier Ltd. All rig h ts rese rv e d .

For exam ple, M ichael addition of JV-acyim ethylpyridinium

ylides to 2 -m eth y l-l,4 -n ap h th o q u in o n e, follow ed by a -b ro m in a￾tion w ith respect to the keto group, dehydrobrom ination and het￾ero-D iels-A lder cyclization has been reported to furnish

pyranonaphthoquinones, albeit in rath er low yields due to a cum ­

bersom e brom ination step .' An im provem ent of this synthetic

strategy involved the use of 2-(phenoxym ethyl)naphthoquinone,

allow ing for a m ore straightforw ard approach to pyranonaphtho￾quinone structures due to th e less reactive (and th u s m ore control￾lable) nature of the phenoxy m oiety as a leaving group.8 A nother

variant of this approach w as based on th e M ichael addition of

N -acylm ethylpyridinium ylides to 2 -(l-h y d ro x y e th y l)-l,4 -n a p h ­

thoquinone, affording in term ed iate hem iacetals prone to undergo

p-toluenesulfonic acid-m ediated d eh y d ratation to yield the desired

naphtho[2,3-c]pyran-5,10-diones.9 A synthetically different

approach com prised transform ation of 2 -b ro m o -l,4 -n ap h th o ­

quinone into 3 -ally l-2 -(l-h y d ro x y eth y l)-l,4 -d im eth y o x y n ap h -

thalene via a nu m b er of steps, w hich th en u n d erw en t subsequent

Lem ieux-Johnson oxidation, oxidative dem ethylation and acid￾catalyzed dehydration to produce 1-m ethylpentalongin. ” O ther

routes tow ard th e lH -benzo[g]isochrom ene-5,10-dione scaffold

involve for exam ple the reaction of im ines w ith 2 -(l-h y d ro x -

y alk y l)-l,4 -n a p h th o q u in o n es" and an intram olecular Heck

reaction of 3-bro m o -2 -fo rm y l-l,4 -d im eth o x y n ap h th alen e w ith 3-

h y d ro x y b u t-l-e n e.12 Intensive efforts have also been devoted to

th e synthesis of diverse pyranonaphthoquinone natural products,