1. Modiﬁcation of post-PKS tailoring steps through combinatorial biosynthesis
Uwe Rix, Carsten Fischer, Lily L. Remsing, Jürgen Rohr *. Nat. Prod. Rep., 2002, 19, 542–580
Epp et al. were able to show that recombination of CarE with either the spiromycin producer S. ambofaciens or S. lividans (exogenously fed spiromycin was necessary) resulted in the formation of the hybrid compound isovaleryl spiromycin. Recently, the acyltransferase encoding gene asm19 from the gene cluster of the ansa-macrolactam maytansine has been identiﬁed through sequence analysis and in-frame deletion. Surprisingly, the corresponding enzyme Asm19 attaches the biologically essential ester side chain of the ansamitocins using N-demethyl-4,5-desepoxymaytansinol as its substrate, and not maytansinol, as was generally believed. Thus, this acyl-transferase acts on a much earlier stage of the maytansin biosynthetic pathway than expected.
2. Total synthesis approaches to natural product derivatives based on the combination of chemical synthesis and metabolic engineering
Andreas Kirschning,* Florian Taft, Tobias Knobloch. Org. Biomol. Chem., 2007, 5, 3245–3259
In principle, the selective expression of late-stage enzymes can be employed for the engineered production of intermediates with desired functionalities suitable for further chemical modiﬁcation and detailed SAR studies. However, intermediates partially lacking peripheral decorations are often accumulated in lower yields than their fully modiﬁed counterparts. Furthermore, omittance of a speciﬁc modiﬁcation in the biosynthetic assembly logicmight interfere with the substrate speciﬁcities of downstream core-decorating enzymes, thus not leading to the accumulation of the desired compound, but to partiallymodiﬁed intermediates.For instance, the inactivation of the acyltransferase in the ansamitocin pathway of Actinosynnema pretiosum did not lead to the expected maytansinol, but to its N-demethyl-desepoxy analogue.
3. Industrial natural product chemistry for drug discovery and development
Armin Bauer*, Mark Bronstrup*. Nat. Prod. Rep.,2014, 31,35–60
As also observed for other tubulin-binding anti-cancer agents, this interaction led to arrest in the G2-M phase of the cell cycle and subsequently to apoptosis. Early clinical trials with 65 were initiated in the 1970s. However, dose-limiting toxicity and lack of response in the majority of patients enrolled in phase II trials led to the discontinuation of 65 as a single agent for anti-cancer therapy. From the early 1990s on, the maytansinoids were re-investigated for their use as toxic payloads for antibodies. 66 was chosen as the starting material for semisynthesis, since it was readily available from fermentation. DM1 68 and other relatedmaytansinoids suitable for conjugation (such as DM4 69) were synthesized from may- tansinol 67, which is obtained by reductive cleavage of 66 at the acyloxy function at C3 with LiAlH(OMe)3. Re-esterification of maytansinol with several carboxylic acids mediated by DCC/ZnCl2 led to new derivatives displaying cytotoxic activity in the 10–90 pMrange, which corresponded to an ideal potency for the use as toxic payloads in antibody conjugates.