Comprehensive review of chemical strategies for the preparation of new aminoglycosides and their biological activities

Abstract

A systematic analysis of all synthetic and chemoenzymatic methodologies for the preparation of aminoglycosides for a variety of applications (therapeutic and agricultural) reported in the scientific literature up to 2017 is presented. This comprehensive analysis of derivatization/generation of novel aminoglycosides and their conjugates is divided based on the types of modifications used to make the new derivatives. Both the chemical strategies utilized and the biological results observed are covered. Structure-activity relationships based on different synthetic modifications along with their implications for activity and ability to avoid resistance against different microorganisms are also presented.

Fig. 1

Structures of AGs discussed in this review. Note: the positions that have been modified on these AGs (as reported in Table 1) are indicated by black numbers.

Fig. 2

Graph showing the increase in the number of publications related to AGs in PubMed (turquoise ovals) and in SciFinder (red ovals) over a 20-year period (1995-2015).

Fig. 3

Overview of the AG modifications, with an AG as a starting point, discussed in each section (2.1-2.8) of this review.

Fig. 4

General strategies for A. the introduction of an electrophilic center at the 5″-position of NEO and at the 6″-position of ABK, AMK, KANA, KANB, and TOB, as well as B. their further modification.

Fig. 5

General strategies for A. the modification of the 5″-position of PAR, and B. the single-step modification of the 6′-position of AMK, KANA, KANB, NEA, NET, SIS, TOB, 6′″-position of PAR, and 4′″-position of AMK.

Fig. 6

Synthetic schemes for A. the single-step modification of the 3-position of AGs (AMK, APR, NEA, NEO, PAR, RIB), and B. the oxidation of the 6′-position of PRM and its many subsequent multistep modifications.

Fig. 7

Oxidation of an allylic amine into an α,β-unsaturated aldehyde.

Fig. 8

Synthesis of A. 3′,4′-dideoxygenated PAR, NEO, and RIB, and B. 3′,4′,3′″,4′″-tetradeoxy-NEO and PAR analogues.

Fig. 9

Synthesis of A. 5-deoxy-5-episubstituted ABK, B. 4″-deoxy-4″-episubstituted ABK, and C. 4′-epimers of PAR.

Fig. 10

Schemes for the preparation of 6″-thioether KANB and TOB derivatives and their oxidation to sulfoxides and sulfones.

Fig. 11

Synthesis of A. homo and hetero 4′,6″- and 3″,6″-dithioether TOB derivatives, and B. homo 6′,5″-dithioether PAR derivatives.

Fig. 12

A. Synthesis of representative 2″-O-alkyl PAR derivatives. B. Examples of 4′- and 4′,6′-O-acetal PAR derivatives.

Fig. 13

Synthesis of 4′-O-alkyl KANA and KANB derivatives, as well as 4″-O-ethyl KANB.

Fig. 14

Synthesis of A. 5-O-alkyl TOB derivatives, B. 5-O-alkyl TOB derivatives by reductive amination (Note: 5-O-alkyl PRM derivatives were also similarly produced), and C. NEA analogues by reductive amination.

Fig. 15

Synthesis of A. NEA derivatives alkylated at their 6-position (Note: an AHB group is shown at the 1-position, but other N-hydroxysuccinimide esters have also been used to derivatized this position), and B. NEA aryl ether derivatives (Note: PRM aryl ether derivatives were also similarly produced).

Fig. 16

Representative schemes for the preparation of A. multialkylated NEB and TOB ether derivatives, B. multialkylated NEB ether derivatives with modified amine groups (Note: PAR and TOB ether derivatives were also similarly produced), and C. multialkylated NEB ether derivatives with imidazole decoration.

Fig. 17

Synthesis of 1-N-derivatized NEA.

Fig. 18

Examples of NEO and TOB derivatives linked via a triazole.

Fig. 19

Examples of KANA, NEO, and TOB derivatives linked via amides.

Fig. 20

Examples of AMK, KANA, NEA, and NEO derivatives linked via carbamates and ethers.

Fig. 21

Representative scheme for the single-step synthesis of 6′″-acylated NEO analogues (Note: PAR derivatives were also similarly produced).

Fig. 22

Scheme for the preparation of AMK, KANA, NET, SIS, and TOB N-acylated analogues.

Fig. 23

Representative schemes for the preparation of A. KANA N-hydroxyurea analogues (Note: TOB derivatives were also similarly produced), and B. PLZ.

Fig. 24

Schemes for the synthesis of A. 6″-N-acyl ABK derivatives, and B. a 4″-N-acyl-4″-epi ABK derivative.

Fig. 25

Representative scheme for the preparation of N-aryl/acylated O-sulfonated NEO analogues (Note: APR and KANA derivatives were also similarly produced).

Fig. 26

Representative schemes for the preparation of A. NEA-CoA conjugates (Note: KANA- and RIB-CoA conjugates were also similarly produced), and B. truncated NEA-bisubstrate inhibitors.

Fig. 27

Synthetic schemes for the preparation of A. sulfonamide-, sulfoxide-, or sulfone-linked NEA-CoA conjugates, and B. a phosphonate-linked PRM-CoA conjugate.

Fig. 28

A. Scheme for the preparation of NEA-CoA conjugates. B. Examples of NEA-pantetheine conjugates.

Fig. 29

Synthetic methodology for the preparation of NEO-CAM and NEO-LNZ conjugates.

Fig. 30

Representative schemes for the preparation of A. TOB-CAM and TOB-CLN conjugates, and B. NEO-CIP conjugates.

Fig. 31

Representative scheme for the preparation of NEO-small molecule conjugates.

Fig. 32

Examples of NEO-bisbenzimidazole conjugates.

Fig. 33

A. Representative scheme for the preparation of a KANA-oligonucleotide (2mer) conjugate (Note: a NEO-oligonucleotide (2mer) conjugate was also similarly produced). B. Structure of a NEO-oligonuceotide (7mer) conjugate.

Fig. 34

Schemes for the preparation of A. NEO-nucleobase conjugates, and B. NEO-NHS ester conjugates.

Fig. 35

Synthesis of NEO-biotin conjugates.

Fig. 36

Representative scheme for the preparation of a PAR-PAMAM-G4 dendrimer conjugate (Note: NEA- and NEO-PAMAM-G4 dendrimer conjugates were also similarly produced).

Fig. 37

Examples of NEO-mono- and bisbenzimidazole conjugates.

Fig. 38

Synthetic schemes for the preparation of A. a TOB-EDTA conjugate, B. a NEO-biotin conjugate, and C. a TOB-PEG conjugate.

Fig. 39

Synthetic schemes for the preparation of A. a NEO-fluorescein conjugate, B. a NEO-methidium conjugate, and C. a NEO-Pt conjugate.

Fig. 40

Representative schemes for the preparation of A. PAR-thiazole orange conjugates (Note: NEA-pyrene and PAR-pyrene conjugates were also similarly produced), and B. NEA-β-carboline conjugates.

Fig. 41

Scheme for the preparation of NEA-nucleotide conjugates via amide coupling.

Fig. 42

Examples of A. NEA-aromatic ring conjugates with amide linkages, B. NEA-small molecule conjugates with amide linkages, and C. NEO-capped aromatic platforms.

Fig. 43

Representative schemes for the preparation of A. NEO-lipid conjugates via amide coupling (Note: KANA- and PAR-lipid conjugates were also similarly produced), and B. a NEO-Ru^II conjugate.

Fig. 44

A. Representative scheme for the preparation of guanidino-NEO-BODIPY conjugates (Note: guanidine-TOB-BODIPY conjugates were also similarly produced). B. Examples of NEA-adenine bisubstrate inhibitors.

Fig. 45

Representative schemes for the preparation of NEO-acridine conjugates (Note: KANA- and TOB-acridine conjugates were also similarly produced).

Fig. 46

Representative schemes for the preparation of A. PAR-nucleobase conjugates (Note: NEO-nucelobase conjugates were also similarly produced), and B. a NEO derivative-thymine conjugate.

Fig. 47

Schemes for the preparation of A. a NEO-peptide library, and B. NEO-peptide nucleic acid conjugates.

Fig. 48

A. Representative scheme for the preparation of a NEA-arginine conjugate (Note: a NEA-lysine conjugate was also similarly produced). B. Examples of AG (KANA, NEA, NEO, and PAR)-arginine conjugates (Note: GEN C₁-arginine conjugates were also reported).

Fig. 49

Representative schemes for the preparation of A. NEO-lysine conjugates (Note: other amino acids have also been conjugated to NEA by using this synthetic methodology), and B. NEO-peptide triazole conjugates.

Fig. 50

Representative scheme for the preparation of NEO-TOB heterodimers by using a disulfide linkage (Note: KANA-KANA, NEO-NEO, TOB-TOB homodimers and KANA-TOB and NEO-TOB heterodimers were also similarly produced).

Fig. 51

Representative schemes for the preparation of A,B. a NEA homodimer via amide coupling (Note: other linkers have also been used to similarly produce additional NEA homodimers).

Fig. 52

Schemes for the preparation of A. NEO homodimers by using carbamate and thiocarbamate linkages, and B. a NEA homodimer by using a carbamate linkage.

Fig. 53

Representative schemes for the preparation of A. a NEO homodimer by epoxide ring opening (Note: a NEO-TOB heterodimer was also similarly produced), and B. NEA homodimers by epoxide ring opening (Note: NEB homodimers were also similarly produced).

Fig. 54

Representative scheme for the preparation of a NEO homodimer conjugated to biotin via click chemistry (Note: a TOB homodimer conjugated to biotin was also similarly produced).

Fig. 55

Representative schemes for the preparation of A. NEO homodimers via click chemistry, B. arginine-linked NEO homodimers via click chemistry, and C. a NEO-peptide homodimer via click chemistry (Note: a KANA-peptide homodimer was also similarly produced).

Fig. 56

Representative schemes for the preparation of A. a conformationally-restricted SIS homodimer via imine formation, and B. a PAR homodimer linked by a quinacridine intercalator via imine formation (Note: analogous KANA and TOB homodimers were also similarly produced).

Fig. 57

Synthetic scheme for the preparation of a PRM homodimer by using nucleophilic substitution reaction.

Fig. 58

Synthetic scheme for the preparation of a conformationally-restricted NEA by amide coupling.

Fig. 59

Schemes for the preparation of conformationally-restricted NEO/PAR derivatives by nucleophilic substitution reaction.

Fig. 60

Representative schemes for the preparation of A. conformationally-restricted KANA derivatives by nucleophilic substitution reaction, B. a conformationally-restricted KANA derivative by ring-closing metathesis, and C. a conformationally-restricted PAR derivative by ring-closing metathesis (Note: a conformationally-restricted PAR derivative with a 5-carbon bridge was similarly produced).

Fig. 61

Schemes for the preparation of A. NEO pseudo-pentasaccharides, and B. 4′-O-glycoside PAR derivatives via glycodiversification.

Fig. 62

Schemes for the preparation of A. PRM pseudo-trisaccharides, B. G418 pseudo-trisaccharides, and C. pyranmycin (pseudo-trisaccharide) derivatives via glycodiversification.

Fig. 63

Representative scheme for the preparation of 4′-modified KANB via glycodiversification.

Fig. 64

Scheme for the preparation of A. KANB derivatives, B. amphiphilic KANB derivatives for antifungal activity, and C. TOB derivatives via glycodiversification.

Fig. 65

Chemoenzymatic modification of NEA, NEO, and PAR by BtrH/BtrG.