Saframycins, structure

Figure 6.23 (a) Saframycin structure and (b) the proposed biosynthetic pathway for... 

The Pictet-Spengler reaction has been carried out on various solid support materials " and with microwave irradiation activation.Diverse structural analogues of (-)-Saframycin A have been prepared by carrying out the Pictet-Spengler isoquinoline synthesis on substrates attached to a polystyrene support. Amine 20 was condensed with aldehyde 21 followed by cyclization to give predominantly the cis isomer tetrahydroisoquinoline 22 which was further elaborated to (-)-Saframycin A analogues. 

A strategy similar to that described above has been used for the total synthesis of saframycin A by Fukuyama and co-workers (90JA3712, 90TL5989). The aldol condensation has been extensively used in the synthesis of bicyclomycin (85JA3253 83TL5627), neoechinulin A(80TL2817), etc. The X-ray structure and photoelectron spectra of cyclo(dehydro-Ala)2 have been determined (85T2015). 

The structures of these compounds were assigned primarily by spectroscopic methods. The recrystalization of the natural Et A12-oxide (67) and the 21 -G-methyl-A12-formyl derivative of compound 63 gave single crystals and allowed X-ray analysis of these systems [74]. The absolute stereochemistry of 70 was determined by chiral GC of the L-Cys unit and by ROESY spectrum of its acetyl derivative [75]. The structures of Et s are related to the microbially derived safracins and saframycins -antitumor agents first isolated from cultured Streptomyces species [76] -as well as to the sponge metabolites renieramycin and xestomycin [77]. 

It was found that 1 acted as an antimitotic agent, not binding to tubulin, but by disorganizing the microtubule network in some fashion. In addition, it is a DNA minor groove guanine-specific alkylating agent [1]. The Et s showed potent inhibition of DNA and RNA synthesis and of RNA polymerase activity, but its inhibition of DNA polymerase activity is much less marked [75]. The potent activity of Et s was attributed, at least in part, to the unit C since the related saframycin A lacks this unit and has lower efficacy than Et 729 in comparable tumor models [74, 75]. More recent structural information on Et 743-DNA adduct was obtained by NMR spectroscopy [78]. An enantioselective total synthesis of Et 743 has been achieved by Corey et al. [79]. 

E (431) and F (432), were isolated from the Palau sponge Rertiera sp. (353). The structures of renieramycins A-D previously found in a sponge of the same genus (354) were reassigned to 433-436, in which the stereochemistry is identical with that of saframycins, metabolites of Streptomyces sp. whose structures were based on X-ray analysis (355). 

To date, only two purely NRPS biosynthetic machineries have been reported from myxobacteria. The first NRPS pathway to be characterized (and the first myxobacterial gene cluster to be identified) directs the biosynthesis of the DNA-binding antibiotic and antitumor agent saframycin Mxl 30 in M. xanthus Its heterocyclic quinone structure originates from a linear peptide intermediate 27 (Ala-Gly-Tyr-Tyr), which is synthesized by a tetramodular assembly line composed of two multifunctional NRPSs, SafA and SafB (Figure 10). It is likely that the tyrosine precursor is modified to 3-hydroxy-5-methyl-0-methyltyrosine through hydroxylation as well as O- and C-methylation reactions, before the monomer is loaded onto the NRPS complex. Once the tetrapeptide structure (27) is constructed, chain release by the last module of the assembly line should occur. However, in SafA, the typical C-terminal TE domain is substituted with a putative... 

To date, the saframycin biosynthetic pathway from M. xanthus remains only partially characterized. A single modifying enzyme, the 0-methyltransferase SafC, assumed to be involved in methyltyrosine formation, has been located adjacent to the two NRPSs (SafA and SafB). Presumably, additional enzymes involved in postassembly line decoration are located adjacent to safA—C, but have not yet been identified. Pseudomonas fluorescens A2-2 and Streptomyces / wW cNRRL 11002 produce the structurally related compounds saffacin B (SAC-B) and saframycin A (SFM-A), and the complete biosynthetic pathways of these metabolites have been cloned and characterized. Compared to the SafA/SafB NRPS complex from M. xanthus, both assembly lines consist of three NRPS proteins (SacA—C and SfmA—C) and, remarkably, different and individual biosynthetic strategies for the formation of the Ala-Gly-Tyr-Tyr tetrapeptide intermediate were proposed for each of these three systems. ... 

Structural similarity of the compounds to known microbial products. An example of this is ecteinascidin 729 (Scheme 32), derived from the ascidian Ecteinascidia turbinata (26). This compound is stmcturally similar to the actinomycete-pro-duced saframycin a (Scheme 33) and related compounds (57)... 

Saframycins. An antibiotic complex (to date 22 known components) from cultures of Streptomyces la-vendulae. The S. contain tetrahydroisoquinoline units dimerized via a piperazine structure. They have anti-neoplastic activity and are active against Gram-positive bacteria, e. g., S. B C2gH3,N308, Mr 537.57, orange prisms, mp. 108-109 C, [a]g,°-54.4° (CH3OH). 

The Pictet-Spengler reaction has also been developed on solid-support materials. This advancement provided the opportunity for the synthesis of an array of structurally diverse analogues of saframycin A, an important anti-tumor antibiotic. 

Scheme 1. Structures of selected members of the ecteinascidin (1-4) and saframycin (5-8) families of natural products.

FIGURE 11.66 Saframycin A structure and 3,9-diazabicyclo[3.3.1]non-6-ene core. (From Myers, A.G. and Lanman, B.A., A solid-supported, enantioselective synthesis suitable for the rapid preparation of large numbers of diverse stractural analogs of (-)-saframycin A, 7. Am. Chem. Soc., 124, 12969, 2002 Orain, D., Koch, G., and Giger, R., From solution phase studies to solid-phase synthesis a new indole based scaffold for combinatorial chemistry, Chimia, 57, 255, 2003.)... 

Myers, A.G. and Lanman, B.A., A solid-supported, enantioselective synthesis suitable for the rapid preparation of large numbers of diverse structural analogs of (-)-saframycin A, J. Am. Chem. Soc., 124, 12969, 2002. 

---