Saframycins

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. 

This quinone synthesis was used to obtain the isoquinoline quinone 2, a unit of some saframycin antibiotics (equation I). 

Several characterized NRPSs utilize alternative methods for chain termination. In some synthetases, the TE domain of the final module is replaced by an NAD(P)H-dependent reductase domain. Reduction of a peptidyl-S-PCP substrate through a two-electron reaction leads to the formation of a transient aldehyde, which is subsequently converted into a cyclic imine or hemiaminal through intramolecular cyclization. This two-electron reaction is utilized in the biosynthesis of nostocyclopeptides, the saframycins, ° and anthramycin. Alternatively, a four-electron reduction to the primary alcohol is observed in the biosynthesis of mycobacterial peptidolipids, linear gramicidin," " the myxalamides, lyngbyatoxin, " and myxochelin A 75,76 alternative four-electron reduction pathway involving aldehyde formation, transamination, and reduction to a primary amine occurs in the biosynthesis of myxochelin B. ... 

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]. 

In relation to their biosynthesis, it was proposed that A-B units of Et s are most likely formed by condensation of two Dopa-derived building blocks and that the tetrahydroisoquinoline ring in unit B is closed by condensation (Pictet-Spengler) with a serine(or glycine)-derived aldehyde, as in the case of the related saframycins. S-Adenosylmethinonine is the likely source of the methyl groups. A plausible route for the formation of unit C was proposed later [75]. This was partially demonstrated by incorporation of radiolabeled tyrosine and cysteine by Kerr and Miranda [80] and by incorporation of labeled methionine, glycine and tryptophan by Morales and Rinehart [81]. 

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). 

Figure 15.11 Enantioselective solid-phase synthesis of saframycin analogs by the Myers group [36, 39, 40],...

The efficiency and practicality of pseudoephedrine-based asymmetric alkylation reactions has been exploited in syntheses of several complex natural products, including cylindrocyclo-phane A, fumonisin B2, pironetin, epothilones A and B, salicylihalamide A, 6,7-dideoxysqualestatin H5, saframycin A,34,35 gjjjj terpestacin. ... 

Jin, W., Metobo, S., Wiiiiams, R. M. Synthetic Studies on Ecteinascidin-743 Constructing a Versatiie Pentacyciic intermediate for the Synthesis of Ecteinascidins and Saframycins. Org. Lett. 2003, 5, 2095-2098. 

Myers and Lanman [405] have reported the preparation of stractural analogs of Saframycin on a soHd support (Scheme 120). 

The desired Saframycin analog was thus prepared in an extraordinary 53% overall yield for a ten-step sequence. Besides the compound shown, 22 additional analogs were prepared, 16 of them by simultaneous parallel synthesis. 

Saframycin belongs to a family of complex polycyclic alkaloids endowed with spectacular antiproliferative activity. The successful demonstration that analogues of the natural product are clinically effective for the treatment of solid tumors has stimulated intense efforts towards the total synthesis and medicinal chemistry of these alkaloids. Myers and Lanman adapted their solution phase synthesis of saframycin to a ten-step solid phase synthesis, leading to the preparation of 16 analogues [40]. The key steps are two Pictet-Spengler reactions, which are used... 

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... 

Figure 10 Nonribosomal peptide biosynthesis in myxobacteria (a). Biosynthesis of saframycin Mx1 (30) in Myxococcus xanthus DM504/15. The tetramoduiar assembiy iine foiiows textbook biochemistry, except for the unusuai reductive chain reiease by the terminai Red domain. The iinear peptide chain (27) then undergoes severai cyciization steps (the underiying mechanisms are not fuiiy understood) and is further decorated with functionai groups (highiighted in gray) by enzyme activities, which have not been identified to date. Based on the absence of E domains in the assembiy iine and the absoiute configuration of the end product 30, an L-configuration was assigned to the incorporated amino acids.

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