Info

Aromatic b-Amino Acids - b-Phenylalanine, b-Tyrosine, and b-3,4-Dihydroxyphenylalanine

Several valued terpene alkaloids [86] from Taxaceae bear b-Phe 8 or a-hydroxy-b-Phe (phenylisoserine) side-chains at C13 and C5. Often these aromatic b-amino acids are N-methylated, as exemplified by a-hydroxylated Winterstein's acid, found to be a side-chain of taxine A 42 (Scheme 1.5.7). The N-benzoylphenylisoserine ester moiety of paclitaxel (taxol) has been found to be essential for its crucial mi-crotubuli-stabilizing activity. Accordingly synthetic taxol derivatives [97] that have already reached the market (e.g. non-natural docetaxel (40, taxotere)) or are still undergoing clinical/preclinical trials, e.g. non-natural BAY 59-8862/IDN5109 41

Scheme 1.5.6. Synthetic taxoides.

[98, 99], still bear an a-hydroxy-b-amino acid side-chain at C13 (Scheme 1.5.6). Clearly, chemistry programs aiming at modification of the taxol phenylisoserine side-chain have significantly stimulated b-amino acid chemistry in general [20]. Up to now free b-Phe 8 has not been isolated from natural sources [88].

The (S)-b-Phe or (S)-b-Tyr substructures of several spermidine alkaloids from plants, for example (S)-periphylline 43 [100, 101] or the spermine derivatives (S)-verbascenine 51 [101], aphelandrine 52 [102], chaenorhine 56 [103] and chae-norpine [104], hint at Michael addition of the biogenic amine to cinnamic acid 48 (or some oxidized equivalent, e.g. 49) within the b-amino amide-forming step

Scheme 1.5.7. Natural products related to jS-Phe 8.

aphelandrine (52) (S)-buchnerine (55); R = OCH3 chaenorhine (56)

Scheme 1.5.8. Spermine alkaloids and their proposed [105] biosynthesis via Michael addition.

aphelandrine (52) (S)-buchnerine (55); R = OCH3 chaenorhine (56)

Scheme 1.5.8. Spermine alkaloids and their proposed [105] biosynthesis via Michael addition.

(Scheme 1.5.8). In fact, as recent investigations by Hesse [105] have shown, proto-verbine 53 and its hydroxy analog prelandrine 54 seem to be exemplary key intermediates within a not yet fully characterized ensemble of closely related biogenetic pathways that are governed by alternating Michael additions and P-450 oxidation steps. The alkaloids 50-56 demonstrate Nature's impressive ability to set up a multitude of highly diverse core structures by selective C-C, C-N and C-O bond-forming steps, only using simple starting materials that are not at all diverse.

b-Tyr substructures are, moreover, found within several peptidic antibiotics, for example the edeines 57 from Bacillus brevis, or within cyclodepsipeptides that have been isolated from marine sponges, for example jaspamides A-C 59 [106] or geo-diamolides H-I 58 [107] (Scheme 1.5.9). The chondramides 60 are closely related antibiotics that have been obtained from the myxobacterium Chondromyces croca-tus. Within the edeine biosynthesis D-b-Tyr 9 seems to be a real precursor [89]. The biosynthesis of the jaspamides, the geodiamolides, or the chondramides has not yet been investigated.

Although L-Dopa is not a proteinogenic a-amino acid, L-b-Dopa 10 is discussed here, because of its close structural and biosynthetic relationship with L-b-Tyr 9 and L-b-Phe 8.

Scheme 1.5.9. Natural peptides and cyclodepsipeptides related to b-Tyr 9.

jaspamide ( (jasplakinolide)

Scheme 1.5.9. Natural peptides and cyclodepsipeptides related to b-Tyr 9.

The chromoproteine antibiotic C-1027 [108] from Streptomyces globisporus has antitumor activity, unfortunately correlated with strong cytotoxicity that hampers the use of this lead structure class as a drug; which is a general problem in cancer drug development (Scheme 1.5.10). The labile chromophor 61 (C-1027-Chr) con-

chromophor Scheme 1.5.10. Alkaloids related to b-Dopa 10

sists of a highly strained nine-membered enedyine ring, the DNA-cleaving tox-ophor [109], that is clamped by an (S)-3-chloro-b-Dopa moiety. Recent investigations of the C-1027 biosynthesis gene cluster [110] show that (S)-3-chloro-b-Dopa really is the biosynthetic precursor of C-1027-Chr 61. The b-amino acid seems to be activated for attachment (with the enedyine alcohol) as a thio ester of a peptidyl-carrier-protein (3-chloro-b-Dopa-S-PCP).

Steglich [111] recently isolated significant amounts of free (R)-b-Dopa 10 from Cortinarius violaceus, a mushroom globally found in the temperate climate zones. Analogous to classical iron ink, the blue violet color of this fungus is created by iron(iii) complexes of (R)-b-Dopa 62 and 63, that seem to form a pH-dependent equilibrium. The biosynthesis of (R)-b-Dopa 9 will be discussed in chapter 1.6.3

0 0

Post a comment