Angucyclines: Biosynthesis, mode-of-action, new natural products, and synthesis

Abstract

Covering: 1997 to 2010. The angucycline group is the largest group of type II PKS-engineered natural products, rich in biological activities and chemical scaffolds. This stimulated synthetic creativity and biosynthetic inquisitiveness. The synthetic studies used five different strategies, involving Diels-Alder reactions, nucleophilic additions, electrophilic additions, transition-metal mediated cross-couplings and intramolecular cyclizations to generate the angucycline frames. Biosynthetic studies were particularly intriguing when unusual framework rearrangements by post-PKS tailoring oxidoreductases occurred, or when unusual glycosylation reactions were involved in decorating the benz[a]anthracene-derived cores. This review follows our previous reviews, which were published in 1992 and 1997, and covers new angucycline group antibiotics published between 1997 and 2010. However, in contrast to the previous reviews, the main focus of this article is on new synthetic approaches and biosynthetic investigations, most of which were published between 1997 and 2010, but go beyond, e.g. for some biosyntheses all the way back to the 1980s, to provide the necessary context of information.

Fig. 1

Landomycin E and landomycin A biosynthetic gene clusters from S. globisporus 1912 (lnd genes, A) and S. cyanogenus S136 (lan genes, B), respectively.

Fig. 2

Engineered landomycin–urdamycin hybrid molecules.

Fig. 3

Landomycin analogues generated through the manipulation of biosynthetic pathways.

Fig. 4

The urdamycin biosynthetic gene cluster.

Fig. 5

Prejadomycin C-glycosides.

Fig. 6

The crystal structure of UrdGT2 (Mittler et al.)

Fig. 7

The aromatic substitution mechanism of the UrdGT2-catalyzed C-glycosylation.

Fig. 8

Chromophore-modified urdamycin A congeners isolated from S. fradiae Tü2717.

Fig. 9

Urdamycins isolated from natural producer S. fradiae and from engineered mutant strains.

Fig. 10

The biosynthetic gene cluster of jadomycin.

Fig. 11

The biosynthetic gene cluster of gilvocarcins.

Fig. 12

Engineered gilvocarcin derivatives.

Fig. 13

Angucycline N-heterocycles.

Fig. 14

Bioactive jadomycins produced by mutasynthesis.

Fig. 15

Selected representatives of the gilvocarcin-class of antitumor antibiotics.

Fig. 16

Depiction of gilvoarcin V 122 cross-linked with thymine residue and histone H3.

Fig. 17

Representative members of the kinamycins (206, 208, and 203), and isoprekinamycin (236).

Fig. 18

Marmycins A (238) and B (239).

Fig. 19

Representative landomycin-type antibiotics.

Fig. 20

Urdamycin derivatives with xanthine oxidase inhibitory properties.

Fig. 21

Structures of structurally more complex new angucyclinones.

Fig. 22

New natural or genetically engineered landomycins.

Fig. 23

New members of the saquamycin family.

Fig. 24

New urdamycin analogues.

Fig. 25

Unique new angucyclines.

Scheme 1

Two different pathways for biosynthesis of the typical benz[a]anthracene backbone of the angucycline group of natural products.

Scheme 2

The incorporation of ¹⁸O-labeled precursor in landomycin A.

Scheme 3

Alternatives for the proposed biosynthetic pathway for landomycin E (14) via 11-deoxylandomycinone (13).

Scheme 4

The proposed pathway for biosynthesis of the NDP-d-olivose and NDP-l-rhodinose building blocks in context with landomycin biosynthesis.

Scheme 5

The proposed biosynthetic pathway for landomycins A and E.

Scheme 6

The generation of sugar chain extended urdamycin A and B analogues through the expression of lanGT4 in S. fradiae TU2717.

Scheme 7

The biosynthetic steps catalyzed by UrdM during urdamycin A (31) biosynthesis.

Scheme 8

The proposed biosynthetic pathway of different urdamycins.

Scheme 9

The biosynthetic pathways for NDP-d-olivose and NDP-l-rhodinose.

Scheme 10

O-glycosylation of alizarin catalyzed by UrdGT2.

Scheme 11

Generation of urdamycin P through the activity of engineered GTs.

Scheme 12

The proposed role of the polyketide synthase genes in jadomycin biosynthesis.

Scheme 13

Investigation of jadomycin A and B biosynthesis.

Scheme 14

The interconversion of jadomycin diastereomers.

Scheme 15

The biosynthetic pathway of l-digitoxose and 6-deoxy-l-altrose in the jadomycin pathway.

Scheme 16

The originally suggested oxidative ring cleavage and vinyl group formation based on incorporation experiments with isotope-labeled precursors.

Scheme 17

The biosynthetic pathway of gilvocarcins.

Scheme 18

The biosynthetic pathway of natural (154, 157, 161 and 165) and engineered (155, 162 and 163) sugar moieties of gilvocarcins (157 and 155), chrysomycins (154), ravidomycins (165 and 161), olivosyl-gilvocarcins (162) and polycarcins (163).

Scheme 19

The proposed pathway for oviedomycin biosynthesis.

Scheme 20

The proposed pathway for gaudimycin biosynthesis.

Scheme 21

The proposed pathway for azicemicin A biosynthesis.

Scheme 22

The biosynthesis of 2-thiotrehalose-6-phosphate (192).

Scheme 23

The proposed pathway for the biosynthesis of 2-thio-d-glucose-6-phosphate (190) and TDP-l-rhodinose (20).

Scheme 24

The proposed pathway for the biosynthesis of BE-7585A (198).

Scheme 25

The proposed pathway for the biosynthesis of kinamycin D (205).

Scheme 26

The proposed pathway for hatomarubigin D (215) biosynthesis.

Scheme 27

The proposed glycosylation sequence of saquayamycin Z (222).

Scheme 28

The proposed mechanism of action for the formation of activated radical species EN30 (237) for interaction with DNA.

Scheme 29

Kaliappan’s total synthesis of YM181741 (334).

Scheme 30

Kaliappan’s total synthesis of (+)-ochromycinone (343), (+)-rubiginone B₂ (344),(-)-tetrangomycin (9), MM-47755 (345).

Scheme 31

The synthesis of 3′-desmethyl-4′-acetyl-marmycin A analogues.^,

Scheme 32

The Guingant synthesis of 5-aza-angucyclinones.

Scheme 33

An alternative strategy for the synthesis of 5-aza angucyclinones by Valderrama et al.

Scheme 34

Ishikawa’s total synthesis of (±)-methyl-kinamycin C (380).

Scheme 35

Mal’s total synthesis of BE-23254 (387).

Scheme 36

Synthesis of 1-O-methyl-defucogilvocarcin M (393) by Mal et al.

Scheme 37

Mal’s total synthesis of chartarin (398).

Scheme 38

The synthesis of O-methylhayumicinone (404).

Scheme 39

Mal’s total synthesis of arnottin I (409).

Scheme 40

Snieckus’s total synthesis of defucogilvocarcin M (147), E (148), and V (149).

Scheme 41

Snieckus’s total synthesis of arnottin I (409).

Scheme 42

Nicolaou’s total synthesis of kinamycin C (208), F (203), and J (428).

Scheme 43

The synthesis of landomycinone (241) by Roush and Neitz.

Scheme 44

The total synthesis of landomycin A (4) by Yu and co-workers.

Scheme 45

Porco’s total synthesis of kinamycin C (208).

Scheme 46

The synthesis of prekinamaycin (201).

Scheme 47

The synthesis C-3′ desmethyl analogues of marmycin A.

Scheme 48

Herzon’s total synthesis of kinamycin F (203).

Scheme 49

Suzuki’s total synthesis of ravidomycin V (123).

Scheme 50

Ishikawa’s synthesis of arnottin I (409) and dimethyl jadomycin A 481.

Scheme 51

Cheng’s total synthesis of arnottin I (409).

Scheme 52

Groth’s total synthesis of (−)-tetrangomycin (9).

Scheme 53

Roulland’s attempt toward the total synthesis of landomycinone.

Scheme 54

Asao’s total synthesis of (+)-ochromycinone (343) and (+)-rubiginone B₂ (344).

Scheme 55

O’Doherty’s total synthesis of jadomycin A (95) and of carbasugar analogue 515 of jadomycin B (96).

Scheme 56

Suzuki’s total synthesis of defucogilvocarcin M (147).

Scheme 57

Suzuki’s total synthesis of PD116740 (272).