Synthesis, Cytotoxicity, and Genotoxicity of 10-Aza-9-oxakalkitoxin, an N,N,O-Trisubstituted Hydroxylamine Analog, or Hydroxalog, of a Marine Natural Product

Abstract

We describe the synthesis of 10-aza-9-oxakalkitoxin, an N,N,O-trisubstituted hydroxylamine-based analog, or hydroxalog, of the cytotoxic marine natural product kalkitoxin in which the -NMe-O-moiety replaces a -CHMe-CH 2 -unit in the backbone of the natural product. 10-Aza-9-oxakalkitoxin displays potent and selective cytotoxicity (IC 50 2.4 ng mL −1 ) comparable to that of kalkitoxin itself (IC 50 3.2 ng mL −1 ) against the human hepato-carcinoma cell line HepG2 over both the human leukemia cell line CEM and the normal hematopoietic CFU-GM. Like kalkitoxin, and contrary to the common expectation for hydroxylamines, 10-aza-9-oxakalkitoxin is not mutagenic.

En Route to the Transformation of Glycoscience: A Chemist’s Perspective on Internal and External Crossroads in Glycochemistry

“…Total synthesis, involving construction of the hydroxylamine unit by two back-to-back reductive amination sequences, afforded 10-aza-9-oxakalkitoxin 91, which showed a small increase in cytotoxicity toward HepG2 over the parent, and is the first kalkitoxin analog with enhanced activity (Figure 10). 156 With the potential of the hydroxalogs established, we turned to improved synthetic methods for their construction, first drawing an analogy with Rychnovsky's ether synthesis. 157 Accordingly, readily accessible N-hydroxy secondary amines were condensed with carboxylic acids to give O-acyl-N,N-dialkyl hydroxylamines 92, which were reduced with DIBAL in dichloromethane before quenching with acetic anhydride.…”

The Powerful Symbiosis Between Synthetic and Medicinal Chemistry

“…This offers the possibility of both improving physicochemical properties and exploring bond vectors that are not accessible from benzene itself. An intriguingly simple bioisostere of aliphatic hydrocarbons has been reported recently by Dhanju et al [19]. They describe substituted hydroxylamines -NMe-O-as chemically stable and nongenotoxic replacements of the -CHMe-CH 2 -group, with the advantage of lacking the stereocenter.…”

Synthesis of O-tert-Butyl-N,N-disubstituted Hydroxylamines by N–O Bond Formation

“…3 More recently, we applied the hydroxalog concept to the synthesis of a potent anticancer derivative 10-aza-9-oxakalkitoxin (IC 50 = 2.4 ng/ mL), a kalkitoxin analog with an activity comparable to that of the parent compound (IC 50 = 3.2 ng/mL) against the human hepatocarcinoma cell line HepG2. 1,7,8 Encouraged by these results, we focused on developing a method for the preparation of N,N,O-trisubstituted hydroxylamines by direct N−O bond formation, thereby facilitating access to the hydroxalog moiety for use as a tool in medicinal chemistry. Adapting earlier methods for ether synthesis, 9,10 we reported 11 a novel method for the construction of N,N,Otrisubstituted hydroxylamines whereby magnesium amides react with methyltetrahydro-2H-pyran (MTHP) monoperoxyacetals to afford N,N,O-trisubstituted hydroxylamines with broad functional group tolerance.…”

“…We have identified the N,N,O -trialkylhydroxylamine unit as an under-represented functional group in medicinal chemistry that is suitable for the bioisosteric replacement of ether and branched alkyl units in natural products (Figure ). − This concept was first applied to the synthesis of a hydroxalog (hydroxylamine analog) of the β-(1 → 3)-glucan laminaritriose, which showed an improved biological activity compared to that of the parent trisaccharide . More recently, we applied the hydroxalog concept to the synthesis of a potent anticancer derivative 10-aza-9-oxakalkitoxin (IC 50 = 2.4 ng/mL), a kalkitoxin analog with an activity comparable to that of the parent compound (IC 50 = 3.2 ng/mL) against the human hepatocarcinoma cell line HepG2. ,, …”

“…In view of the importance of the tert- butyl group in medicinal chemistry and agrochemistry (Figure ) − and the recent advances − in bioisosteric replacements of tert- butyl groups, we have devised and report here a method to access a broad range of O - tert -butyl- N,N -disubstituted hydroxylamines. Effectively, we sought a simple protocol to overcome the inherent limitations of our earlier method, enabling further investigation of the hydroxalog , concept.…”