Naphthoquinone antibiotics

Quinones of various degrees of complexity have antibiotic, antimicrobial, and anticancer activities, eg, a2iddinornitosene [80954-63-8] (36), (-)-2-methyl-l,4-naphthoquinone 2,3-epoxide [61840-91 -3] (37), and doxombicin [23214-92-8] (adriamycin) (38) (see Antibiotics Chemotherapeutics, anticancer), ah of these natural and synthetic materials have stimulated extensive research in synthetic chemistry. 

Nanaomycin A 103 and deoxyfrenolicin 108 are members of a group of naphthoquinone antibiotics based on the isochroman skeleton. The therapeutic potential of these natural products has attracted considerable attention, and different approaches towards their synthesis have been reported [65,66]. The key step in the total synthesis of racemic nanaomycin A 103 is the chemo-and regioselective benzannulation reaction of carbene complex 101 and allylacety-lene 100 to give allyl-substituted naphthoquinone 102 after oxidative workup in 52% yield [65] (Scheme 47). The allyl functionality is crucial for a subsequent intramolecular alkoxycarbonylation to build up the isochroman structure. However, modest yields and the long sequence required to introduce the... 

Danishefsky et al. succeeded in preparing the benz[a] anthracene core structure 111 of angucycline antibiotics by performing a benzannulation reaction with the cycloalkynone 109 [69]. Deprotonation of the naphthoquinone 110 with DBU yields the desired anthraquinone 111 (Scheme 49). 

Wang YC, Li WY, Wu DC, Wang JJ, Wu CH, Liao JJ, Lin CK. (2009) In vitro activity of 2-methoxy-l, 4-naphthoquinone and stigmasta-7,22-diene-3P-ol from Impatiens balsamina L. against multiple antibiotic-resistant Helicobacter pylori. Evid Based Complement. Alternat Med 9 1-8. 

Conjugate addition of acyl groups to naphthoquinones (3, 211).2 The acyl nickel carbonylate anion (1) undergoes conjugate addition to the ethylene ketal 2 to form a lithium adduct that can be trapped by allyl iodide to give 3 in 81% yield. This product can be converted in a few steps to the hydroxyquinone 4, a precursor of the naphthoquinone antibiotic deoxyfrenolicin (5). 

Isomarinone (1679), an isomer of the previously known marinone (7), was isolated from the same tropical sediment bacterium (1638). Another marine-derived bacterium related to the genus Streptomyces has yielded the novel azamerone (1680) (1639). The British Columbian medicinal plant Moneses uniflora contains the antibiotic 8-chlorochimaphilin (1681), which is more active than chimaphilin (1640). Sesame roots (Sesamum indicum) have yielded the red chlorinated naphthoquinone chlorosesamone (1682) (1641). Cultures of Streptomyces strain LL-A9227 produce chloroquinocin (1683), which has some antibacterial activity against Gram-positive bacteria (1642). The two xestoquinones 1684 and 1685 were characterized from the Philippino sponge Xestospongia sp., and display topoisomerase II activity (1643). 

He H, Yang HY, Luckman SW, Roll DM, Carter GT (2002) Chloroquinocin, a Novel Chlorinated Naphthoquinone Antibiotic from Streptomyces sp., LL-A9227. J Antibiot 55 1072... 

Several synthetic compounds containing the naphthoquinone skeleton, such as 2-(4-cyclohexylcyclohexyl)-3-hydroxy- 1,4-naphthoquinone [169], are effective in the treatment of coccidial infection. Two structurally related antibiotics WS-5995A (36) and WS-5995B (37a), isolated from S. auranticolor sp. nov. near Tokyo, efficiently protect Eimeria tenella (a species of coccidia) infection. An inactive component WS-5995C (37b) can be readily converted to the active (36) by simple dehydration [ 170-172]. Compound (36), the structure of which resembles the aforementioned benz[a]anthraquinone antibiotics, is the first example of a 5//-benzo[d ]naphtho[ 2,3-6 ]pyran ring system found in nature. 

Pathirana, C., Jensen, P. R., and Fenical, W., Marinone and debromomarinone antibiotic sesquiter-penoid naphthoquinones of a new structure class from a marine bacterium, Tetrahedron Lett., 33, 7663, 1992. 

M. F. Semmelhack, J. J. Bozell, L. Keller, T. Sato, E. Spiess, W. Wulff, and A. Zask, Synthesis of Naphthoquinone Antibiotics by Intramolecular Alkyne Cycloaddition to Carbene-Chromium Complexes, Tetrahedron 41, 5803-5812 (1985). 

Several hundred semisynthetic derivatives have been prepared in an effort to obtain substances with better biological activities (for references see Ref.s)). Particularly positions 3 and 4 of the naphthoquinone ring system (numbering system as proposed by Prelog7 8) have been extensively substituted, since it has been shown that structural changes in these two positions do not critically affect the action of the substance on the target enzyme, the bacterial RNA polymerase (cf. Chapter 3.). They can, however, influence other parameters such as its ability to penetrate into cells, its pharmacokinetic properties and resorption, which are all important for clinical use as an antibiotic. Rifampicin (U.S. rifampin), which is a widely used orally active tuberculostatic agent, is a 3-(4-methyl piperazinyl)-iminomethyl derivative of rifamycin SV, synthesized via the 3-formyl derivative (Fig. 5)10 ... 

First applications of this chemistry were reported by Semmelhack et al., who synthesized the (racemic) naphthoquinone antibiotics nanao-mycin A (rac-lQ, R = Me) and desoxyfrenolicin (rac-10, R = propyl). These target molecules are retrosynthetically traced back to a precursor of type 11 [5]. In these cases, the Pd-catalyzed cycli-zations proceeded only with low diastereoselec-tivity the desired trarti -stereochemistry, however, can be set up by subsequent equilibration. 

Couquelet J, Tronche P, Niviere P, Andraud G (1963) Antibiotic activity of an isomer of patulin and of a homolog. Trav Soc Pharm Montpellier 23 214-219 Holshouser MH, Loeffler LJ, Hall IH (1981) Synthesis and anti-tumor activity of a series of sulfone analogs of 1,4-naphthoquinone. J Med Chem 24 853-858... 

Isochromans. - The antibiotic ( )-nanaomycin A (111) has been synthesized by two routes from 2-bromo-8-methoxy-l,4-naphthoquinone. Readily accesssible indanones have been converted into isochromans, which have been elaborated into 9-demethoxyeleutherin (112) and 9-deoxynanaomycin A methyl ester (113). Some pharmacological interest has appeared in l-(piper-... 

A similar strategy has been followed for the preparation of the naphthoquinone nucleus (118) [202], a precursor of awamycin (119), another ansamycin antibiotic isolated from several Streptomyces species and active against Gram-positive bacteria, protozoa and marine tumors in vivo. The compound is also cytotoxic to Hela cells in vitro [203]. The structure of awamycin (119) has been determined by X-ray analysis [204] and it is structurally similar to damavaricin D (120), a degradation product and biosynthetic precursor of streptovaricin D (108). 

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