- Modular Total Synthesis of iso-Archazolids and Archazologs
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Full details on the design, development, and successful implementation of suitable synthetic strategies directed toward the total synthesis of iso-archazolids and archazologs are reported. Both a biomimetic and a multistep total synthesis of iso-archazolid B, the most potent and least abundant archazolid, are described. The bioinspired conversion from archazolid B was realized by a high-yielding 1,8-Diazabicyclo[5.4.0]undec-7-ene catalyzed one-step double-bond shift. A highly stereoselective total synthesis was accomplished in 25 steps, involving a sequence of highly stereoselective aldol reactions, an efficient aldol condensation to forge two elaborate fragments, and a challenging ring-closing metathesis macrocyclization with an unusual Stewart-Grubbs catalyst. These strategies proved to be generally useful and could be successfully implemented for the preparation of three novel iso-archazolids as well as five novel archazologs, lacking the thiazole side chain. A wide variety of further archazolids and archazologs may now be targeted for exploration of the promising anticancer potential of these polyketide macrolides.
- Dedenbach, Simon,Menche, Dirk,Rivière, Solenne,Ruiz, Johal,Scheeff, Stephan
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p. 10190 - 10223
(2021/08/16)
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- PROCESS FOR THE SYNTHESIS OF (2E, 4E, 6Z, 8E)-8-(3,4-DIHYDRONAPHTHALEN-1(2H)-YLIDENE)-3,7-DIMETHYLOCTA-2, 4, 6-TRIENOIC ACID
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This invention relates to a novel method for the synthesis of (2E,4E,6Z,8E)-8-(3,4- dihydronaphthalen-1 (2H)-ylidene)-3,7-dimethylocta-2,4,6-trienoic acid. In particular, the invention relates to several improvements in several individual steps of the multi- step synthesis scheme
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Paragraph 0097
(2017/10/13)
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- Synthesis of apo-13- and apo-15-lycopenoids, cleavage products of lycopene that are retinoic acid antagonists
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Consumption of the tomato carotenoid, lycopene, has been associated with favorable health benefits. Some of lycopene's biological activity may be due to metabolites resulting from cleavage of the lycopene molecule. Because of their structural similarity to the retinoic acid receptor (RAR) antagonist, β-apo-13-carotenone, the "first half" putative oxidative cleavage products of the symmetrical lycopene have been synthesized. All transformations proceed in moderate to good yield and some with high stereochemical integrity allowing ready access to these otherwise difficult to obtain terpenoids. In particular, the methods described allow ready access to the trans isomers of citral (geranial) and pseudoionone, important flavor and fragrance compounds that are not readily available isomerically pure and are building blocks for many of the longer apolycopenoids. In addition, all of the apo-11, apo-13, and apo-15 lycopenals/lycopenones/lycopenoic acids have been prepared. These compounds have been evaluated for their effect on RAR-induced genes in cultured hepatoma cells and, much like β-apo-13-carotenone, the comparable apo-13-lycopenone and the apo-15-lycopenal behave as RAR antagonists. Furthermore, molecular modeling studies demonstrate that the apo-13-lycopenone efficiently docked into the ligand binding site of RARα. Finally, isothermal titration calorimetry studies reveal that apo-13-lycopenone acts as an antagonist of RAR by inhibiting coactivator recruitment to the receptor.
- Narayanasamy, Sureshbabu,Sun, Jian,Pavlovicz, Ryan E.,Eroglu, Abdulkerim,Rush, Cassandra E.,Sunkel, Benjamin D.,Li, Chenglong,Harrison, Earl H.,Curley, Robert W.
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p. 1021 - 1029
(2017/05/17)
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- Conformationally Defined Rexinoids and Their Efficacy in the Prevention of Mammary Cancers
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(2E,4E,6Z,8Z)-8-(3′,4′-Dihydro-1′(2H)-naphthalen-1′-ylidene)-3,7-dimethyl-2,3,6-octatrienoinic acid (UAB30) is currently undergoing clinical evaluation as a novel cancer prevention agent. In efforts to develop even more highly potent rexinoids that prevent breast cancer without toxicity, we further explore here the structure-activity relationship of two separate classes of rexinoids. UAB30 belongs to the class II rexinoids and possesses a 9Z-tetraenoic acid chain bonded to a tetralone ring, whereas the class I rexinoids contain the same 9Z-tetraenoic acid chain bonded to a disubstituted cyclohexenyl ring. Among the 12 class I and class II rexinoids evaluated, the class I rexinoid 11 is most effective in preventing breast cancers in an in vivo rat model alone or in combination with tamoxifen. Rexinoid 11 also reduces the size of established tumors and exhibits a therapeutic effect. However, 11 induces hypertriglyceridemia at its effective dose. On the other hand rexinoid 10 does not increase triglyceride levels while being effective in the in vivo chemoprevention assay. X-ray studies of four rexinoids bound to the ligand binding domain of the retinoid X receptor reveal key structural aspects that enhance potency as well as those that enhance the synthesis of lipids.
- Atigadda, Venkatram R.,Xia, Gang,Deshpande, Anil,Wu, Lizhi,Kedishvili, Natalia,Smith, Craig D.,Krontiras, Helen,Bland, Kirby I.,Grubbs, Clinton J.,Brouillette, Wayne J.,Muccio, Donald D.
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p. 7763 - 7774
(2015/10/20)
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- METHOD FOR MANUFACTURING PHOSPHONOCROTONIC ACID DERIVATIVE
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Provided is a method of manufacturing a high quality phosphonocrotonic acid derivative. The present invention is a method of manufacturing a compound represented by the following Formula (3) by reacting a compound represented by the following Formula (1) with a compound represented by the following Formula (2), which comprises a treatment process using an acid or base. [in the formula, R1 represents a C1-6 linear or branched alkyl group that may be substituted by a C6-10 aryl group, a C2-6 linear or branched alkenyl group that may be substituted by a C6-10 aryl group, a C2-6 linear or branched alkynyl group that may be substituted by a C6-10 aryl group, or a C6-10 aryl group, R2 represents a hydrogen atom, or a C1-6 linear or branched alkyl group that may be substituted by a C6-10 aryl group, R3 represents a C1-6 linear or branched alkyl group, a C6-10 aryl group, or a halogen atom, and X represents a halogen atom, and multiple R1s may be the same or different].
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Paragraph 0143-0145
(2014/03/24)
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- Tailoring 3,3'-dihydroxyisorenieratene to hydroxystilbene: Finding a resveratrol analogue with increased antiproliferation activity and cell selectivity
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Four novel compounds were designed by "tailoring" 3,3'-dihydroxyisorenieratene (a natural carotenoid) based on an isoprene unit retention truncation strategy. Among them, the smallest molecule 1 (2,3,6,2',3',6'-hexamethyl-4,4'-dihydroxy-trans-stilbene) was concisely synthesized in a one-pot Stille-Heck tandem sequence, and surfaced as a promising lead molecule in terms of its selective antiproliferative activity mediated by blocking the NCI-H460 cell cycle in G1 phase. Additionally, theoretical calculations and cell uptake experiments indicate that the unique polymethylation pattern of compound 1 significantly induces a conformational change shift out of planarity and increases its cell uptake and metabolic stability. The observation should be helpful to rationally design resveratrol-inspired antiproliferative agents. Four novel compounds were designed by "tailoring" 3,3'-dihydroxyisorenieratene (a natural carotenoid) based on an isoprene unit retention truncation strategy. Among them, the smallest molecule 1 was concisely synthesized by a one-pot Stille-Heck tandem sequence, and surfaced as a promising lead molecule in terms of its selective antiproliferative activity (see figure).
- Kang, Yan-Fei,Yan, Wen-Jing,Zhou, Ting-Wen,Dai, Fang,Li, Xiu-Zhuang,Bao, Xia-Zhen,Du, Yu-Ting,Yuan, Cui-Hong,Wang, Hai-Bo,Ren, Xiao-Rong,Liu, Qiang,Jin, Xiao-Ling,Zhou, Bo,Zhang, Jie
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supporting information
p. 8904 - 8908
(2014/07/22)
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- Syntheses, antiproliferative activity and theoretical characterization of acitretin-type retinoids with changes in the lipophilic part
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Acitretin analogs, incorporating changes in the lipophilic part, were efficiently synthesized from commercially available aromatic aldehydes or methyl ketones using the Wittig or Horner-Wadsworth-Emmons reaction. Their antiproliferative activity was evaluated against human breast MCF-7 epithelial cells. Analogs 3, 4, 8 and 11 exhibited strong, dose-dependent, antiproliferative activity on the tested cell line. Analog 3, incorporating three methoxy groups in the aromatic ring, exhibited the strongest inhibitory effect at 10 μM. High-level all electron conventional ab initio and density functional theory quantum chemical calculations were performed to obtain the molecular structure, electron charge distribution and polarization properties of all compounds of interest in this work. The most active analogs were planar and were characterized by larger dipole moments than the other synthesized molecules. Another factor of importance to the analysis of the activity of these molecules is the dipole polarizability.
- Magoulas, George E.,Bariamis, Stavros E.,Athanassopoulos, Constantinos M.,Haskopoulos, Anastasios,Dedes, Petros G.,Krokidis, Marios G.,Karamanos, Nikos K.,Kletsas, Dimitris,Papaioannou, Dionissios,Maroulis, George
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experimental part
p. 721 - 737
(2011/03/20)
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- Development of a synthesis of lankacidins: an investigation into 17-membered ring formation
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Studies are reported concerning the synthesis of macrocyclic analogues of the lankacidins.The long-chain trienylphosphonate 33 has been synthesized as a mixture of epimers at C(7), by a convergent route which involved alkylation of ethyl 2-methyl-3-oxobutanoate 10 by the 10-(tert-butyldimethylsilyloxy)-3,9-dimethyldeca-2,4,8-trienyl chloride 11 to give 27 followed by an aldol addition to the aldehyde 12.Stereoselective reduction then gave the 1,3-syn-diol 35 which was protected as its acetonide 36.However, it did not prove possible to hydrolyse the 1,3-dioxolane ring in 36 to reveal the keto phosphate grouping and leave the acetonide component intact.To avoid this problem, acrolein was added to the alkylated keto ester 27 to give the aldol product 40 as a mixture of diastereoisomers.Stereoselective reduction gave the 1,3-syn-diols 41 and 42, in a ratio of 75:25, which were separated and taken through to the δ-lactones 47 and 48.The lactone 47 corresponds to the C(14)-C(12) fragment of the lankacidins, and the diol 41 is an advanced intermediate for a synthesis of a 17-membered macrocyclic analogue of the lankacidins.The diols 41 and 42 were protected as their acetonides 43 and 44 and these were taken through to the 16-formyl-2-oxophosphonates 7 and 57.Cyclisations into the cycloheptadeca-2,4,8,10-tetraenones 8 and 58 were carried out using potassium carbonate in the presence of 18-crown-6 in toluene at 100 deg C.Alternative conditions for the cyclisations were less successful as were attempts to cyclise the halogeno sulfones 62 and 63 although the 17-acetoxy sulfone 64 was cyclised using tetrakis(triphenylphosphine)palladium(0) and 1,3-bis(triphenylphosphino)propane, but only in a modest yield (18percent).Deprotection and reduction of the cyclised products have been briefly investigated.
- Mata, Ernesto G.,Thomas, Eric J.
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p. 785 - 800
(2007/10/02)
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- A CONVENIENT SYNTHESIS OF (+/-) ASCOCHLORIN
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A convergent total synthesis of (+/-) ascochlorin is described.
- Safaryn, J. E.,Chiarello, J.,Chen, K.-M.,Joullie, M. M.
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p. 2635 - 2642
(2007/10/02)
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