The ICH M7 guideline describes a consistent approach to identify, categorize, and control DNA reactive, mutagenic, impurities in pharmaceutical products to limit the potential carcinogenic risk related to such impurities. This paper outlines a series of principles and procedures to consider when generating (Q)SAR assessments aligned with the ICH M7 guideline to be included in a regulatory submission. In the absence of adequate experimental data, the results from two complementary (Q)SAR methodologies may be combined to support an initial hazard classification. This may be followed by an assessment of additional information that serves as the basis for an expert review to support or refute the predictions. This paper elucidates scenarios where additional expert knowledge may be beneficial, what such an expert review may contain, and how the results and accompanying considerations may be documented. Furthermore, the use of these principles and procedures to yield a consistent and robust (Q)SAR-based argument to support impurity qualification for regulatory purposes is described in this manuscript.
A convergent synthesis of the marine natural product (+)-peloruside has been reported. This target has been assembled through the successive application of two methyl ketone boron aldol addition reactions to the latent C 7 -C 11 dialdehyde synthon. This approach afforded a 22-step synthesis of this natural product. The influence of resident stereocenters on aldol reaction diastereoselection has been examined in detail.Peloruside A (1) is a secondary metabolite of a marine sponge (Mycale genus) collected from Pelorus Sound, New Zealand. In addition to its structure elucidation, the initial disclosure by Northcote 1 also demonstrated peloruside A to be cytotoxic to P388 murine leukemia cells at nanomolar concentrations. Subsequent investigations 2 revealed peloruside's anti-proliferation potency is similar to that exhibited by paclitaxel. The first synthesis of 1, reported by De Brabander, established the absolute stereochemistry of this natural product. 3 In the interim, two additional syntheses have been published. 4,5 The purpose of this communication is to report a convergent approach to this natural product suitable for analogue synthesis.The deconstruction of 1 relies on the two highlighted aldol disconnections illustrated in Scheme 1. Based on prior art, 6 we anticipated that the C 3 and C 15 stereocenters would favorably influence the stereochemical outcome of these two bond constructions. In the following discussion, the syntheses of subunits 3 and 4 will be described along with their elaboration to (+)-peloruside A (1). The synthesis of 5 is included in the Supplementary Information.The synthesis of C 1 -C 6 synthon 3 requires six steps from commercially available (S)-4-benzyl-2-oxazolidinone 7a and is summarized in Scheme 2. Notably, the illustrated imideevans@chemistry.harvard.edu. Supporting Information Available: Experimental details and analytical data including copies of 1 H and 13 C NMR spectra for all new compounds (xx pages) (PDF). The synthesis of methyl ketone 5 is also included. This material is available free of charge via the Internet at http://pubs.acs.org. The synthesis of synthon 4, based on the use of (S)-pantolactone, is summarized in Scheme 3. The chelate-controlled borohydride reduction was quite diastereoselective (95:5); however, competing conjugate reduction was noted as a minor side reaction. NIH Public AccessSelection of the illustrated C 9 hydroxyl configuration in subunit 4 bears comment. On the basis of previous model studies probing the influence of β-oxygen stereocenters on aldehyde face selectivity, 8 we concluded that the (R)-C 3 , (S)-C 8 and (R)-C 9 stereocenters in fragments 3 and 4 would be mutually reinforcing in this double stereodifferentiating aldol addition. A recent study by Paterson documents the diminished selectivities if the other C 9 epimer is employed in a similar aldol addition.9The aldol union of methyl ketone 3 and aldehyde 4 is summarized in Scheme 4. In developing this reaction, we noted a surprising diastereoselectivity dependence on the par...
A close structural analogue of bryostatin 1, which differs from bryostatin 1 only by the absence of the C30 carbomethoxy group (on the C13 enoate of the B-ring), has been prepared by total synthesis. Biological assays reveal a crucial role for substitution in the bryostatin 1 A-ring in conferring those responses which are characteristic of bryostatin 1 and distinct from those observed with PMA.
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