Efficient Synthesis of Glaziovianin A Isoflavone Series from Dill and Parsley Extracts and Their in Vitro/in Vivo Antimitotic Activity.
A concise six-step protocol for the synthesis of isoflavone glaziovianin A (GVA) and its alkoxyphenyl derivatives 9 starting with readily available plant metabolites from dill and parsley seeds was developed. The reaction sequence involved an efficient conversion of the key intermediate epoxides 7 into the respective β-ketoaldehydes 8 followed by their Cu(I)-mediated cyclization into the target series 9. The biological activity of GVA and its derivatives was evaluated using a panel of seven human cancer cell lines and an in vivo sea urchin embryo assay. Both screening platforms confirmed the antimitotic effect of the parent GVA (9cg) and its alkoxy derivatives. Structure-activity relationship studies suggested that compounds 9cd and 9cf substituted with trimethoxy- and dillapiol-derived B-rings, respectively, were less active than the parent 9cg. Of the evaluated human cancer cell lines, the A375 melanoma cell line was the most sensitive to the tested molecules. Notably, the target compounds were not cytotoxic against human peripheral blood mononuclear cells up to 10 μM concentration. Phenotypic readouts from the sea urchin assay unequivocally suggest a direct microtubule-destabilizing effect of isoflavones 9cg, 9cd, and 9cf.
N. D. Zelinsky Institute of Organic Chemistry, RAS , Leninsky Prospect, 47, 119991, Moscow, Russian Federation.
Victor V
VV
Semenov
N. D. Zelinsky Institute of Organic Chemistry, RAS , Leninsky Prospect, 47, 119991, Moscow, Russian Federation.
Dmitry V
DV
Tsyganov
Institute of Developmental Biology, RAS , Vavilov Street, 26, 119334, Moscow, Russian Federation.|Chemical Block Ltd. , 3 Kyriacou Matsi, 3723, Limassol, Cyprus.
Marina N
MN
Semenova
Life Sciences Center, Moscow Institute of Physics and Technology , Institutsky Per., 9, Dolgoprudny, Moscow Region 141700, Russian Federation.
Roman N
RN
Chuprov-Netochin
N. D. Zelinsky Institute of Organic Chemistry, RAS , Leninsky Prospect, 47, 119991, Moscow, Russian Federation.
Mikhail M
MM
Raihstat
N. D. Zelinsky Institute of Organic Chemistry, RAS , Leninsky Prospect, 47, 119991, Moscow, Russian Federation.
Leonid D
LD
Konyushkin
Life Sciences Center, Moscow Institute of Physics and Technology , Institutsky Per., 9, Dolgoprudny, Moscow Region 141700, Russian Federation.
Polina B
PB
Volynchuk
Life Sciences Center, Moscow Institute of Physics and Technology , Institutsky Per., 9, Dolgoprudny, Moscow Region 141700, Russian Federation.
Elena I
EI
Marusich
Life Sciences Center, Moscow Institute of Physics and Technology , Institutsky Per., 9, Dolgoprudny, Moscow Region 141700, Russian Federation.
Vera V
VV
Nazarenko
Life Sciences Center, Moscow Institute of Physics and Technology , Institutsky Per., 9, Dolgoprudny, Moscow Region 141700, Russian Federation.|Institute of Cell Biophysics, RAS , Institutskaya Street, 3, Pushchino, Moscow Region 142290, Russian Federation.
Sergey V
SV
Leonov
Life Sciences Center, Moscow Institute of Physics and Technology , Institutsky Per., 9, Dolgoprudny, Moscow Region 141700, Russian Federation.
Alex S
AS
Kiselyov
D028524:Anethum graveolens / Q000737:chemistry*; D000818:Animals; D050256:Antimitotic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D020650:Combinatorial Chemistry Techniques; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007529:Isoflavones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D015394:Molecular Structure; D028528:Petroselinum / Q000737:chemistry*; D012617:Sea Urchins / Q000187:drug effects; D013329:Structure-Activity Relationship; D050257:Tubulin Modulators / Q000494:pharmacology
D050256:Antimitotic Agents; D000970:Antineoplastic Agents; D007529:Isoflavones; D050257:Tubulin Modulators; C521560:glaziovianin A