Synthesis and Anticancer Activity of the (R,S)‐Benzofused 1,5‐Oxathiepine Moiety Tethered to Purines through Alkylidenoxy Linkers

Abstract

Herein we report the design, synthesis, and anticancer activity of a series of substituted (R,S)-9-[2- or 3-(3,4-dihydro-2H-1,5-benzoxathiepine-3-yloxy)alkyl]-9H-purines. Derivatives with propylenoxy-linked 2',6'-dichloro- and 6'-bromopurines are more active than their respective ethylenoxy-linked purine conjugates. On the other hand, the compound with a propylenoxy-linked 6'-chloropurine is nearly equipotent to the corresponding ethylenoxy-linked conjugate. Our results show that bromo- and chloropurine-conjugated benzoxathiepines containing a propylenoxy linker are able to inhibit PI3 kinase (PI3K) phosphorylation in MCF-7 breast cancer cells, indicating that the activation of eIF2α, together with inhibition of the PI3K pathway, is the mechanism of action by which these compounds effect their antitumor activity in the MCF-7 cell line; apoptosis was induced in a p53-independent manner.

Development of Biotransamination Reactions towards the 3,4-Dihydro-2H-1,5-benzoxathiepin-3-amine Enantiomers

“…We have reported several (RS)-benzo-fused seven-membered rings with oxygen and sulfur atoms in 1,5 relative positions with interesting anti-proliferative activities against the MCF-7 cancer cell line. The most active compounds are 1 and 2 [1] (Figure 1). Other compounds, such as 3 [2] and 4 [3], exhibited more potent anti-ischemic effects than reference compounds, whilst 5 can be the prototype for the design of more potent anti-proliferative agents [4] (Figure 1).…”

“…The incorporation of α-amino acids into heterocyclic structures is an effective strategy for generating numerous peptidomimetics and combinatorial library scaffolds. Benzo-fused seven-membered rings with oxygen and sulphur atoms in 1,5 relative positions (1)(2)(3)(4)(5) with interesting biological properties [1][2][3][4][5]. The (3R)-3,4-dihydro-2H-1,5-benzoxathiepin-3amine core appears in red in compounds 3-5.…”

Novel synthesis of 2H-1,5-benzoxathiepin-3(4H)-one and 5H-4,1-benzoxathiepin-3(2H)-one derivatives and chemical properties evaluation

“…For example, 1,5-benzoxathiepine derivatives exhibit serotonin S 2 -receptor-blocking activity, calcium antagonism, actions to relieve cerebral vasospasm and to improve renal circulation, and diuretic and antithrombotic activities, and are of value as a prophylactic and therapeutic agent for ischemic cardiopathies, thrombosis, hypertension, and cerebral circulatory disorders [8]; can be used for the treatment of glaucoma [9]; and show anticancer activity [10,11]. A number of patents on synthesis and using in medicine were published recently [12,13].…”

Synthesis of [1,4]Oxathiepino[5,6-b]quinolines via Base-Mediated Intramolecular Hydroalkoxylation

“…11,12 Oxathiepines rank among the less studied heterocycles, although groups have reported several compounds possessing (R,S)-benzo-fused, seven-membered rings with oxygen and sulfur atoms in a 1,5-relationship with interesting antiproliferative activities against the MCF-7 cancer cell line (Figure 1). 13,14…”