104224-85-3Relevant academic research and scientific papers
Anti-cancer agents and uses thereof
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Page/Page column 38-39, (2008/12/08)
The present invention is in the area of novel compounds and salts thereof, their syntheses, and their use as anti-cancer agents. The compounds include compounds of Formula I: and solvates, hydrates and pharmaceutically-acceptable salts thereof, wherein A1 is N or CR1; A3 is N or CR3; A5 is N or CR5; R1, R3-R6 and L are defined in the specification; n is 0 or 1; and X is an optionally-substituted aryl group having 6-10 carbons in the ring portion, an optionally-substituted 6-membered heteroaryl group having 1-3 nitrogen atoms in the ring portion, an optionally-substituted 5-membered heteroaryl group having 0-4 nitrogen atoms in the ring portion and optionally having 1 sulfur atom or 1 oxygen atom in the ring portion, or an optionally-substituted heteroaryl group in which a 6-membered ring is fused either to a 5-membered ring or to a 6-membered ring, wherein in each case 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from nitrogen, oxygen and sulfur. They are effective against a broad range of cancers, especially leukemia, prostate, non-small cell lung and colon. They are additionally useful in the treatment of proliferative retinopathies such as diabetic neuropathy and macular degeneration.
ANTI-CANCER AGENTS ANS USES THEREOF
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Page/Page column 110-111, (2010/11/29)
The present invention is in the area of novel compounds and salts thereof, their syntheses, and their use as anti-cancer agents. The compounds include compounds of Formula (I): and solvates, hydrates and pharmaceutically-acceptable salts thereof, wherein A1 is N or CR1; A3 is N or CR3; A5 is N or CR5; R1, R3 R6 and L are defined in the specification; n is 0 or 1; and X is an optionally-substituted aryl group having 6- 10 carbons in the ring portion, an optionally-substituted 6- membered heteroaryl group having 1- 3 nitrogen atoms in the ring portion, an optionally-substituted 5- membered heteroaryl group having 0- 4 nitrogen atoms in the ring portion and optionally having 1 sulfur atom or 1 oxygen atom in the ring portion, or an optionally-substituted heteroaryl group in which a 6- membered ring is fused either to a 5- membered ring or to a 6- membered ring, wherein in each case 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from nitrogen, oxygen and sulfur. They are effective against a broad range of cancers, especially leukemia, prostate, non-small cell lung and colon. They are additionally useful in the treatment of proliferative retinopathies such as diabetic neuropathy and macular degeneration.
Anti-cancer agents and uses thereof
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Page/Page column 39, (2008/06/13)
The present invention is in the area of novel compounds and salts thereof, their syntheses, and their use as anti-cancer agents. The compounds include compounds of Formula I: and solvates, hydrates and pharmaceutically-acceptable salts thereof, wherein A1 is N or CR1; A3 is N or CR3; A5 is N or CR5; R1, R3—R6 and L are defined in the specification; n is 0 or 1; and X is an optionally-substituted aryl group having 6-10 carbons in the ring portion, an optionally-substituted 6-membered heteroaryl group having 1-3 nitrogen atoms in the ring portion, an optionally-substituted 5-membered heteroaryl group having 0-4 nitrogen atoms in the ring portion and optionally having 1 sulfur atom or 1 oxygen atom in the ring portion, or an optionally-substituted heteroaryl group in which a 6-membered ring is fused either to a 5-membered ring or to a 6-membered ring, wherein in each case 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from nitrogen, oxygen and sulfur. They are effective against a broad range of cancers, especially leukemia, non-small cell lung and colon.
Synthesis and structure-activity relationships of a new series of retinoid-related biphenyl-4-ylacrylic acids endowed with antiproliferative and proapoptotic activity
Cincinelli, Raffaella,Dallavalle, Sabrina,Nannei, Raffaella,Carella, Serena,De Zani, Daniele,Merlini, Lucio,Penco, Sergio,Garattini, Enrico,Giannini, Giuseppe,Pisano, Claudio,Vesci, Loredana,Carminati, Paolo,Zuco, Valentina,Zanchi, Chiara,Zunino, Franco
, p. 4931 - 4946 (2007/10/03)
Atypical retinoids (AR) represent a class of proapoptotic agents with promising potential in the treatment of neoplastic diseases. In the present work 4′-hydroxybiphenyl-4-ylacrylic acids were studied as a novel series of AR. The synthesized compounds were evaluated for their antiproliferative activity in a human promyelocytic leukemia cell line (NB4) and in an ovarian carcinoma cell system including IGROV-1, carrying a functional wild-type p53, and a cisplatin-resistant subline, IGROV-1/Pt-1. The presence of a bulky lipophilic group at position 3′ (adamantan-1-yl being the best) and the E configuration of the acrylic moiety appear essential for activity below 1 μM. No substitution on the rings or on the double bond improved the activity. A qualitative correlation between the log P and molecular volume of the 3′-substituent and the antiproliferative activity was found. From the study of a few selected compounds, it appears that the presence of the carboxylic group is an essential requirement for apoptogenic properties but not for antiproliferative activity, this being maintained in amide derivatives. On the other hand, compounds able to induce apoptosis produced a detectable level of genotoxic damage. This observation supports the hypothesis that the genotoxic stress is a critical event mediating apoptosis induction by compounds of this class. Among the compounds investigated, E-3-(3′-adamantan-1-yl-4′- hydroxybiphenyl-4-yl)acrylic acid (2) was chosen for further investigation.
Use of a RAR-gamma-specific agonist ligand for increasing the rate of apoptosis
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, (2008/06/13)
The present invention relates to the use of at least one RAR receptor agonist ligand, particularly 6-[3-(adamantan-1-yl)-4-(prop-2-ynyloxy)phenyl]naphthalene-2-carboxylic acid or 5-[(E)-3-oxo-3-(5,5,8,8-tetrahydronaphthalene-2-yl)propenyl]thiophene-2-carb
Heterocyclic derivatives for the treatment of cancer and other proliferative diseases
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, (2008/06/13)
The invention relates to certain heterocyclic compounds useful for the treatment of cancer and other diseases, having the Formula (I): wherein: (a) m is an integer 0 or 1; (b) R12 is an alkyl, a substituted alkyl, a cycloalkyl, a substituted cycloalkyl, a heterocyclic, a substituted heterocyclic, a heteroaryl, a substituted heteroaryl, an aryl or a substituted aryl residue; (c) Ar3 is an aryl, a substituted aryl, a heteroaryl or a substituted heteroaryl residue; (d) Ar4 is an aryl, a substituted aryl, a heteroaryl or a substituted heteroaryl residue; (e) R5 is hydrogen, hydroxy, alkyl or substituted alkyl; (f) - - - - - represents a bond present or absent; and (g) W, X, Y and Z are independently or together C(O)—, C(S), S, O, or NH; or a pharmaceutically acceptable salt thereof.
Synthesis, structure-affinity relationships, and biological activities of ligands binding to retinoic acid receptor subtypes
Charpentier,Bernardon,Eustache,Millois,Martin,Michel,Shroot
, p. 4993 - 5006 (2007/10/03)
The retinoic acid receptors (RARs) transduce retinoid dependant gene regulation, and many biological effects of retinoids are mediated through binding and activation of three closely related receptor subtypes (RARα, RARβ, and RARγ). In order to investigate the role of receptor subtypes, we have carried out a chemical synthesis program to seek selective retinoids for these receptors. We measured receptor binding affinity using recombinant RARα, -β, and -γ proteins and assessed cellular differentiating activity in F9 murine teratocarcinoma cells (F9 cells). This research has identified the 4-substituted-3-(1-adamantyl)phenyl moiety as a new pharmacophore which can replace the β-cyclogeranylidene ring of the naturally ocurring all- trans-retinoic acid. Two chemical series derived from the general structures 6-(3-tertioalkyl-phenyl)-2-naphthoic acid (series I) and 4-[(E)-2-(3- tertioalkylphenyl)propenyl]benzoic acid (series II) were developed. In particular, we have obtained the RARγ selective derivatives 6-[3-(1- adamantyl)-4-hydroxyphenyl]-2-naphthoic acid (7) [K(i)(RARα) = 6500 nM, Ki(RARβ) = 2480 nM, K(i)(RARγ) = 77 nM] and 4-[(E)-2-[3-(1-adamantyl)-4- hydroxyphenyl]propenyl]benzoic acid (19) [K(i)(RARα) = 1 144 nM, K(i)(RARβ) = 1245 nM, K(i)(RARγ) = 53 nM]. In series I, the presence of a phenol group, irrespective of the nature of tertioalkyl group, imparted at least partial RARγ selectivity, whereas in series II, the presence of both adamantyl and phenol groups is needed to confer RARγ selectivity. The RARγ selective ligands induce differentiation in F9 cells (7, AC50 = 33 nM; 19, AC50 = 66 nM). From series I, a mixed RARβ-γ agonist with potent cellular differentiating activity was selected for development as a topical antiacne agent, 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid (5, CD 271) [K(i)(RARα) = 1100 nM, K(i)-(RARβ) = 34 nM, K(i)(RARγ) = 130 nM, AC50(F9) = 37 nM]. Finally, from series II, we have obtained a weak antagonist in the F9 cellular differentiation assay, 4-[(E)-2-(3-tert-butyl- 4-hydroxyphenyl)propenyl]benzoic acid (15, IC50 = 700 nM).
