Indoloquinolizidine Derivatives as Novel and Potent Apoptosis Inducers and Cell‐Cycle Blockers

Abstract

A collection of approximately 11 000 natural-product derived and inspired compounds was screened for potential apoptosis inducers in the human tumour cell lines HepG2 (liver), HeLa (cervix) and MCF-7 (breast) by means of MTT and ATP-luminescence assays, automated cell counting, caspase 3/7 assay as well as by fluorescence activated cell sorting (FACS) analysis. A group of seven indoloquinolizidine derivatives was identified that exhibited IC(50) values for cell proliferation as low as 2 mumol L(-1), with no major necrosis of cells detectable. At the same time, an increase in the rate of apoptosis of up to 600 % relative to the reference level was observed. FACS analysis indicated that these effects are related to an arrest of cells in the G(2)M phase of the cell cycle.

Indolo[2,3-a]quinolizidines and Derivatives: Bioactivity and Asymmetric Synthesis

“…-partial agonist of opioid receptors, high affinity and selectivity for µ-opioid receptors [34] -high affinity for μ-and δ-opioid receptors [36] -affinity for opioid receptors [37] 24 -affinity for opioid receptors [37] -potential apoptosis inducers in three human tumor cell lines (HeLa, MCF-7 and HepG2 cell lines) [38] - optically active indoloquinolizidine natural products based on asymmetric catalysis. This approach is highly efficient and productive.…”

“…This type of reaction in structurally complex molecule synthesis has several intrinsic advantages: multiple bond formation, time and cost efficiency, atom economy, 38 environmental sustainability as well as applicability to diversity-oriented high-throughput synthesis. Since the synthetic effort toward natural products and other interesting compounds usually requires the introduction of several stereogenic centers, the design of cascades to provide specific targeted molecules of structural and stereochemical complexity constitutes a significant intellectual challenge.…”

Scandium(III)‐Zeolites as New Heterogeneous Catalysts for Imino‐Diels–Alder Reactions

“…On the other hand, indoloquinolizidine alkaloids such as reserpine, yohimbine hirsutine, and corynantheidol (Scheme 7) exhibit various and interesting properties, mostly due to their interaction with adrenoceptors in the nervous system. [33] Some derivatives have also been developed as apoptosis inducers [34] or as inhibitors for protein tyrosine phosphatase B. [35] Such compounds could be obtained in a three-step sequence, with a Diels-Alder type reaction on imine derived from tryptophane or tryptamine, followed by intramolecular cyclization (Scheme 8).…”

“…Whatever the starting amino acid, the ratios were indeed very similar, with a 3 to 1 mixture, whereas the solution or resin phase synthesis gave ratios from 1 to 1 to 91 to 9. NMR studies of the adducts (and especially of the cyclized products (see below) as well as comparison with the few related known compounds), [34] allowed the assignment of the diastereoisomer stereochemistry as shown in Table 4.…”

Diastereoselective Synthesis of 3-Alkylindoloquinolizine Derivatives via Regiospecific Oxidative Cyclization

“…The indoloquinolizine framework is widely distributed in both pharmaceuticals and natural products (e.g. Figure 1) showing a wide range of pharmacological activities such as analgesic, 1 anti-inflammatory, 2 antihypertensive, 3 anticancer, 4 apoptosis inducers, 5 anti-leishmanial, 6 among others. majority of reported strategies for asymmetric total synthesis of indoloquinolizidine alkaloids have required multistep syntheses relying on starting materials from the chiral pool.…”