Design and in vitro activities of N -alkyl- N -[(8- R -2,2-dimethyl-2 H -chromen-6-yl)methyl]heteroarylsulfonamides, novel, small-molecule hypoxia inducible factor-1 pathway inhibitors and anticancer agents

Journal of Medicinal Chemistry

Volumn 55, Issue 15, 2012, Pages 6738-6750

  Mun, Jiyoung ^a   Jabbar, Adnan Abdul ^b   Devi, Narra Sarojini ^b   Yin, Shaoman ^b   Wang, Yingzhe ^c   Tan, Chalet ^c   Culver, Deborah ^a   Snyder, James P ^a   Van Meir, Erwin G ^a,b   Goodman, Mark M ^a  

^a EMORY UNIVERSITY   (United States)

^b EMORY UNIVERSITY SCHOOL OF MEDICINE   (United States)

^c MERCER UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

3,4 DIMETHOXY N [(2,2 DIMETHYL 2H CHROMEN 6 YL) METHYL] N PHENYLBENZENESULFONAMIDE; ANTINEOPLASTIC AGENT; HYPOXIA INDUCIBLE FACTOR 1; N ( CYCLOPENTYL) N [(2,2 DIMETHYL 2H CHROMEN 6 YL) METHYL] PYRIDINE 2 SULFONAMIDE; N (CYCLOBUTYL) N [(2,2 DIMETHYL 2H CHROMEN 6 YL) METHYL] PYRIDINE 2 SULFONAMIDE; N (CYCLOPROPYLMETHYL) N [(2,2 DIMETHYL 2H CHROMEN 6 YL) METHYL] PYRIDINE 2 SULFONAMIDE; N [(2,2 DIMETHYL 2H CHROMEN 6 YL) METHYL] N (2 METHYLPROPYL) 1 METHYL 1H IMIDAZOLE 2 SULFONAMIDE; N [(2,2 DIMETHYL 2H CHROMEN 6 YL) METHYL] N (2 METHYLPROPYL) 1,3 THIAZOLE 2 SULFONAMIDE; N [(2,2 DIMETHYL 2H CHROMEN 6 YL) METHYL] N (2 METHYLPROPYL) PYRIDINE 2 SULFONAMIDE; N [(2,2 DIMETHYL 2H CHROMEN 6 YL) METHYL] N (2 METHYLPROPYL) PYRIDINE 4 SULFONAMIDE; N [(2,2 DIMETHYL 2H CHROMEN 6 YL) METHYL] N (PROPAN 2 YL) ARYLSULFONAMIDE; N [(2,2 DIMETHYL 2H CHROMEN 6 YL) METHYL] N (PROPAN 2 YL) PYRIDINE 2 SULFONAMIDE; N [(8 HYDROXY 2,2 DIMETHYL 2H CHROMEN 6 YL) METHYL] N (PROPAN 2 YL) PYRIDINE 2 SULFONAMIDE; N [(8 HYDROXY 2,2 DIMETHYL 2H CHROMEN 6 YL) METHYL] N (PROPAN 2 YL) PYRIDINE 4 SULFONAMIDE; N [(8 METHOXY 2,2 DIMETHYL 2H CHROMEN 6 YL) METHYL] N (PROPAN 2 YL) PYRIDINE 2 SULFONAMIDE; N [(8 METHOXY 2,2 DIMETHYL 2H CHROMEN 6 YL) METHYL] PYRIDINE 2 SULFONAMIDE; N ALKYL N [(8 R 2,2 DIMETHYL 2H CHROMEN 6 YL) METHYL] HETEROARYLSULFONAMIDE; N CYCLOPROPYL N [(2,2 DIMETHYL 2H CHROMEN 6 YL) METHYL] PYRIDINE 2 SULFONAMIDE; SULFONAMIDE; UNCLASSIFIED DRUG;

ANTINEOPLASTIC ACTIVITY; AQUEOUS SOLUTION; ARTICLE; COMPUTER MODEL; CONTROLLED STUDY; DRUG DESIGN; DRUG EFFICACY; DRUG SOLUBILITY; DRUG STRUCTURE; DRUG SYNTHESIS; HUMAN; HUMAN CELL; IC 50; IN VITRO STUDY; LIPOPHILICITY;

ANIMALS; ANTINEOPLASTIC AGENTS; BENZOPYRANS; CELL HYPOXIA; CELL LINE, TUMOR; CELL PROLIFERATION; DRUG SCREENING ASSAYS, ANTITUMOR; FIBROBLASTS; HUMANS; HYPOXIA-INDUCIBLE FACTOR 1, ALPHA SUBUNIT; MICE; SIGNAL TRANSDUCTION; SOLUBILITY; STEREOISOMERISM; STRUCTURE-ACTIVITY RELATIONSHIP; SULFONAMIDES; TRANSCRIPTION, GENETIC;

EID: 84864930524     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm300752n     Document Type: Article

References (78)

1. Brat, D. J.; Castellano-Sanchez, A. A.; Hunter, S. B.; Pecot, M.; Cohen, C.; Hammond, E. H.; Devi, S. N.; Kaur, B.; Van Meir, E. G. Pseudopalisades in glioblastoma are hypoxic, express extracellular matrix proteases, and are formed by an actively migrating cell population Cancer Res. 2004, 64, 920-927
2. Kaur, B; Brat, D. J.; Devi, S. N.; Van Meir, E. G. Vasculostatin, a natural proteolytic fragment of brain angiogenesis inhibitor 1 is an anti-angiogenic and anti-tumorigenic factor Oncogene 2005, 24, 3638-3642
3. Brat, D. J.; Castellano-Sanchez, A.; Kaur, B.; Van Meir, E. G. Genetic and biologic progression in astrocytomas and their relation to angiogenic dysregulation Adv. Anat. Pathol. 2002, 9, 24-36
4. Giaccia, A.; Siim, B. G.; Johnson, R. S. HIF-1 as a target for drug development Nat. Rev. Drug Discovery 2003, 2, 1-9
5. Melillo, G. Inhibiting hypoxia-inducible factor 1 for cancer therapy Mol. Cancer Res. 2006, 4, 601-605
6. Semenza, G. L. Targeting HIF-1 for cancer therapy Nat. Rev. Cancer 2003, 3, 721-732
7. Poon, E.; Harris, A. L.; Ashcroft, M. Targeting the hypoxia-inducible factor (HIF) pathway in cancer Expert Rev. Mol. Med. 2009, 11, e26
8. Carmeliet, P.; Dor, Y.; Herbert, J.; Fukumura, D.; Brusselmans, K.; Dewerchin, M.; Neeman, M.; Bono, F.; Abramovitch, R.; Maxwell, P.; Koch, C. J.; Ratcliffe, P.; Moons, L.; Jain, R. K.; Collen, D.; Keshert, E. Role of HIF-1α in hypoxia-mediated apoptosis, cell proliferation and tumor angiogenesis Nature 1998, 395, 485-490
9. Favaro, E.; Nardo, G.; Persano, L.; Masiero, M.; Moserle, L.; Zamarchi, R.; Rossi, E.; Esposito, G.; Plabani, M.; Sattler, U.; Mann, T.; Mueller-Klieser, W.; Ciminale, V.; Amadori, A.; Indraccolo, S. Hypoxia inducible factor-1α inactivation unveils a link between tumor cell metabolism and hypoxia-induced cell death Am. J. Pathol. 2008, 173, 1186-1201
10. Kilic, M.; Kasperczyk, H.; Fulda, S.; Debatin, K. M. Role of hypoxia inducible factor-1 alpha in modulation of apoptosis resistance Oncogene 2007, 26, 2027-2038
11. Schelter, F.; Gerg, M.; Halbgewachs, B.; Schaten, S.; Gorlach, A.; Schrotzlmair, F.; Kruger, A. Identification of a survival-independent metastasis-enhancing role of hypoxia-inducible factor-1α with a hypoxia-tolerant tumor cell line J. Biol. Chem. 2010, 285, 26182-26189
12. Mendez, O.; Zavadil, J.; Esencay, M.; Lukyanov, Y.; Santovasi, D.; Wang, S.; Newcomb, E. W.; Zagzag, D. Knock down of HIF-1α in glioma cells reduces migration in vitro and invasion in vivo and impairs their ability to form tumor spheres Mol. Cancer 2010, 9, 133-142
13. Hadjipanayis, C. G.; Van Meir, E. G. Tumor initiating cells in malignant gliomas: Biology and implications for therapy J. Mol. Med. 2009, 87, 363-374
14. Hadjipanayis, C. G.; Van Meir, E. G. Brain tumor propagating cells: Biology, genetics, and targeted therapies Trends Mol. Med. 2009, 15, 519-30
15. Kaur, B.; Khwaja, F. W.; Severson, E. A.; Matheny, S. L.; Brat, D. J.; Van Meir, E. G. Hypoxia and the hypoxia-inducible-factor pathway in glioma growth and angiogenesis Neuro-Oncology 2005, 7, 106-121
16. Blum, R.; Jacob-Hirsch, J.; Amariglio, N.; Rechavi, G.; Kloog, Y. Ras inhibition in glioblastoma down-regulates hypoxia-inducible factor-1α, causing glycolysis shutdown and cell death Cancer Res. 2005, 65, 999-1006
17. Hung, J. J.; Yang, M. H.; Hsu, H. S.; Hsu, W. H.; Liu, J. S.; Wu, K. J. Prognostic significance of hypoxia-inducible factor-1α, TWIST1 and Snail expression in resectable non-small cell lung cancer Thorax 2009, 64, 1082-1089
18. Eul, B.; Rose, F.; Krick, S.; Savai, R.; Gyal, P.; Klepetko, W.; Grimminger, F.; Weissmann, N.; Seeger, W.; Hanze, J. Impact of HIF-1α and HIF-2α on proliferation and migration of human pulmonary artery fibroblasts in hypoxia FASEB J. 2006, 20, 163-165
19. Rohwer, N.; Lobitz, S.; Daskalow, K.; Jons, T.; Vieth, M.; Schlag, P. M.; Kemmner, W.; Wiedenmann, B.; Cramer, T.; Hocker, M. HIF-1α determines the metastatic potential of gastric cancer cells Br. J. Cancer 2009, 100, 772-781
20. Zhang, J.; Lu, A.; Li, L.; Yue, J.; Lu, Y. p16 Modulates VEGF expression via its interaction with HIF-1α in breast cancer cells Cancer Invest. 2010, 28, 588-597
21. Akakura, N.; Kobayashi, M.; Horiuchi, I.; Suzuki, A.; Wang, J.; Chen, J.; Niizeki, H.; Kawamura, K.; Hosokawa, M.; Asaka, M. Constitutive expression of hypoxia-inducible factor-1α renders pancreatic cancer cells resistant to apoptosis induced by hypoxia and nutrient deprivation Cancer Res. 2001, 61, 6548-6554
22. Cao, X.; Bloomston, M.; Zhang, T.; Frankel, W. L.; Jia, G.; Wang, B.; Hall, N. C.; Koch, R. M.; Cheng, H.; Knopp, M. V.; Sun, D. Synergistic antipancreatic tumor effect by simultaneously targeting hypoxic cancer cells with HSP90 inhibitor and glycolysis inhibitor. Clin Cancer Res. 2008, 14, 1831-1839
23. Dang, D. T.; Chen, F.; Gardner, L. B.; Cummins, J. M.; Rago, C.; Bunz, F.; Kantsevoy, S. V.; Dang, L. H. Hypoxia-inducible factor-1α promotes nonhypoxia-mediated proliferation in colon cancer cells and xenografts Cancer Res. 2006, 66, 1684-1693
24. Zhong, H.; De Marzo, A. M.; Laughner, E.; Lim, M.; Hilton, D. A.; Zagzag, D.; Buechler, P.; Isaacs, W. B.; Semenza, G. L.; Simons, J. W. Overexpression of hypoxia-inducible factor 1α in common human cancers and their metastases Cancer Res. 1999, 59, 5830-5835
25. Li, L.; Lin, X.; Staver, M.; Shoemaker, A.; Semizarov, D.; Fesik, S. W.; Shen, Y. Evaluating hypoxia-inducible factor-1α as a cancer therapeutic target via inducible RNA interference in vivo Cancer Res. 2005, 65, 7249-7258
26. Post, D. E.; Van Meir, E. G. A novel hypoxia inducible factor activated oncolytic adenovirus for cancer therapy Oncogene 2003, 22, 2065-2072
27. Post, D. E.; Devi, N. S.; Li, Z.; Brat, D. J.; Kaur, B.; Nicholson, A.; Olson, J. J.; Zhang, Z.; Van Meir, E. G. Cancer therapy with a replicating oncolytic adenovirus targeting the hypoxic microenvironment of tumors Clin. Cancer Res. 2004, 10, 8603-8612
28. Post, D. E.; Sandberg, E. M.; Devi, S. N.; Brat, D. J.; Xu, Z.; Tighiouart, M.; Van Meir, E. G. Targeted cancer-gene therapy using a HIF-dependent oncolytic adenovirus armed with interleukin-4 Cancer Res. 2007, 67, 6872-6881
29. Yang, L.; Cao, Z.; Li, F.; Post, D. E.; Van Meir, E. G.; Zhong, H.; Wood, W. C. Tumor-specific gene expression using the survivin promoter is further increased by hypoxia Gene Ther. 2004, 11, 1215-23
30. Kim, H.-S.; Peng, G.-Y.; Hicks, J. M.; Weiss, H. L.; Van Meir, E. G.; Brenner, M. K.; Yotnda, P. Engineering human tumor-specific cytotoxic T cells to function in a hypoxic environment Mol. Ther. 2008, 16, 599-606
31. Keith, B.; Johnson, R. S.; Simon, M. C. HIF1α and HIF2α: Sibling rivalry in hypoxic tumour growth and progression Nat. Rev. Cancer 2012, 12, 9-22
32. Li, Z; Bao, S; Wu, Q; Wang, H; Eyler, C; Sathornsumetee, S; Shi, Q; Cao, Y; Lathia, J; McLendon, R. E.; Hjelmeland, A. B.; Rich, J. N. Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells Cancer Cell 2009, 15, 501-513
33. Qiang, L; Wu, T; Zhang, H. W.; Lu, N; Hu, R; Wang, Y. J.; Zhao, L; Chen, F. H.; Wang, X. T.; You, Q. D.; Guo, Q. L. HIF-1alpha is critical for hypoxia-mediated maintenance of glioblastoma stem cells by activating notch signaling pathway Cell Death Differ. 2012, 19, 284-294
34. Kang, S. H.; Cho, H.; Devi, S. N.; Zhang, Z.; Escuin, D.; Liang, Z.; Mao, H.; Brat, D. J.; Olson, J. J.; Simons, J. W.; LaVallee, T. M.; Giannakakou, P.; Van Meir, E. G.; Shim, H. Anti-tumor effect of 2-methoxyestradiol in a rat orthotopic brain tumor model Cancer Res. 2006, 66, 11992-11997
35. Koh, M. Y.; Spivak-Kroizman, T.; Venturini, S.; Welsh, S.; Williams, R. R.; Kirkpatrick, D. L.; Powis, G. Molecular mechanisms for the activity of PX-478, an antitumor inhibitor of the hypoxia-inducible factor-1α Mol. Cancer Ther. 2008, 7, 90-100
36. Wang, X. H.; Cavell, B. E.; Syed Alwi, S. S.; Packham, G. Inhibition of hypoxia inducible factor by phenethyl isothiocyanate Biochem. Pharmacol. 2009, 78, 262-272
37. Chau, N. M.; Rogers, P.; Aherne, W.; Carroll, V.; Collins, I.; McDonald, E.; Workman, P.; Ashcroft, M. Identification of novel small molecule inhibitors of hypoxia-inducible factor-1 that differentially block hypoxia-inducible factor-1 activity and hypoxia-inducible factor-1α induction in response to hypoxic stress and growth factors Cancer Res. 2005, 65, 4918-4928
38. Lee, K; Lee, J. H.; Boovanahalli, S. K.; Jin, Y.; Lee, M.; Jin, X.; Kim, J. H.; Hong, Y. S.; Lee, J. J. Aryloxyacetylamino)benzoic acid analogs: A new class of hypoxia-inducible factor-1 inhibitors J. Med. Chem. 2007, 50, 1675-1684
39. Semenza, G. L. Evaluation of HIF-1 inhibitors as anticancer agents Drug Discovery Today 2007, 12, 853-859
40. Tan, C.; de Noronha, R. G.; Roecker, A. J.; Pyrzynska, B.; Khwaja, F.; Zhang, Z.; Zhang, H.; Teng, Q.; Nicholson, A. C.; Giannakakou, P.; Zhou, W.; Olson, J. J.; Pereira, M. M.; Nicolaou, K. C.; Van Meir, E. G. Identification of a novel small-molecule inhibitor of the hypoxia-inducible factor 1 pathway Cancer Res. 2005, 65, 605-612
41. Belozerov, V.; Van Meir, E. G. Hypoxia Inducible factor-1: A novel target for cancer therapy Anti-Cancer Drugs 2005, 16, 901-909
42. Belozerov, V.; Van Meir, E. G. Inhibitors of hypoxia inducible factor-1 signaling Curr. Opin. Invest. Drugs 2006, 7, 1067-1076
43. Cook, K. M.; Hilton, S. T.; Mecinovic, J.; Motherwell, W. B.; Figg, W. D.; Schofield, C. J. Epidithiodiketopiperazines block the interaction between hypoxia-inducible factor-1alpha (HIF-1alpha) and p300 by a zinc ejection mechanism J. Biol. Chem. 2009, 284, 26831-26838
44. Kung, A. L.; Zabludoff, S. D.; France, D. S.; Freedman, S. J.; Tanner, E. A.; Vieira, A.; Cornell-Kennon, S.; Lee, J.; Wang, B.; Wang, J.; Memmert, K.; Naegeli, H. U.; Petersen, F.; Eck, M. J.; Bair, K. W.; Wood, A. W.; Livingston, D. M. Small molecule blockade of transcriptional coactivation of the hypoxia-inducible factor pathway Cancer Cell 2004, 6, 33-43
45. Lee, K; Zhang, H; Qian, D. Z.; Rey, S; Liu, J. O.; Semenza, G. L. Acriflavine inhibits HIF-1 dimerization, tumor growth, and vascularization Proc. Natl. Acad. Sci. U. S. A. 2009, 106, 17910-17915
46. Tan, C.; de Noronha, R. G.; Devi, N. S.; Jabbar, A. A.; Kaluz, S.; Liu, Y.; Reid-Mooring, S.; Nicolaou, K. C.; Wang, B.; Van Meir, E. G. Sulfonamides as a new scaffold for hypoxia inducible factor pathway inhibitors Bioorg. Med. Chem. Lett. 2011, 21, 5528-5532
47. Nicolaou, K. C.; Pfefferkorn, J. A.; Roecker, A. J.; Cao, G.-Q.; Barluenga, S.; Mitchell, H. J. Natural product-like combinatorial libraries based on privileged structures. 1. General principles and solid-phase synthesis of benzopyrans J. Am. Chem. Soc. 2000, 122, 9939-9953
48. Nicolaou, K. C.; Pfefferkorn, J. A.; Mitchell, H. J.; Roecker, A. J.; Barluenga, S.; Cao, G.-Q.; Affleck, R. L.; Lillig, J. E. Natural product-like combinatorial libraries based on privileged structures. 2. Construction of a 10 000-membered benzopyran library by directed split-and-pool chemistry using nanokans and optical encoding J. Am. Chem. Soc. 2000, 122, 9954-9967
49. Narita, T.; Yin, S.; Gelin, C. F.; Moreno, C. S.; Yepes, M.; Nicolaou, K. C.; Van Meir, E. G. Identification of a novel small molecule HIF-1a translation inhibitor Clin. Cancer Res. 2009, 15, 6128-36
50. Shi, Q.; Yin, S.; Kaluz, S.; Ni, N.; Devi, N. S.; Mun, J.; Wang, D.; Damera, K.; Chen, W.; Burroughs, S.; Reid-Mooring, S.; Goodman, M. M.; Van Meir, E. G.; Wang, B.; Snyder, J. P. Binding model for the interaction of anti-cancer arylsulfonamides with the p300 Transcription co-factor. ACS Med. Chem. Lett. 2012, in press.
51. Yin, S.; Kaluz, S.; Devi, N. S.; Jabbar, A. A.; de Noronha, R. G.; Mun, J.; Zhang, Z.; Boreddy, P. R.; Wang, W.; Wang, Z.; Abbruscato, T.; Chen, Z.; Olson, J. J.; Zhang, R.; Goodman, M. M.; Nicolaou, K. C.; Van Meir, E. G. Arylsulfonamide KCN1 inhibits in vivo glioma growth and interferes with HIF signaling by disrupting HIF-1α interaction with co-factors p300/CBP. Unpublished results.
52. Wang, W.; Rayburn, A. L.; Xu, E. R.; Zhang, H.; Zhang, X.; Wang, X.; Wang, M. H.; Wang, H.; Van Meir, E, G.; Zhang, R. KCN1, a novel synthetic sulfonamide anticancer agent: In vitro and in vivo anti-pancreatic cancer activities and preclinical pharmacology. Unpublished results.
53. Zhang, Q.; Kaluz, S.; Yang, H.; Van Meir, E. G.; Grossniklaus, H. E. Efficacy of the novel small molecule HIF pathway inhibitor KCN1 in the control of micrometastases in experimental ocular melanoma. Unpublished results.
54. Mun, J.; Jabbar, A.; Devi, N.; Liu, Y.; Van Meir, E. G.; Goodman, M. M. Structure-activity relationship of 2,2-dimethyl-2 H -chromene based arylsulfonamide analogs of 3,4-dimethoxy- N -[(2,2-dimethyl-2 H -chromen-6-yl)methyl]- N -phenylbenzenesulfonamide, a novel small molecule hypoxia inducible factor-1 (HIF-1) pathway inhibitor and anti-cancer agent. Bioorg. Med. Chem. [Online early access]. DOI: 10.1016/j.bmc.2012.04.064.
55. Oprea, T. I. Current trends in lead discovery: Are we looking for the appropriate properties? Mol. Diversity 2000, 5, 199-208
56. Perola, E. An analysis of the binding efficiencies of drugs and their leads in successful drug discovery programs J. Med. Chem. 2010, 53, 2986-2997
57. VCCLAB, Virtual computational chemistry laboratory, http://www.vcclab. org, 2005.
58. Tetko, I. V.; Gasteiger, J.; Todeschini, R.; Mauri, A.; Livingstone, D.; Ertl, P.; Palyulin, V. A.; Radchenko, E. V.; Zefirov, N. S.; Makarenko, A. S.; Tanchuk, V. Y.; Prokopenko, V. V. Virtual computational chemistry laboratory-Design and description J. Comput. Aid. Mol. Des. 2005, 19, 453-463
59. Tetko, I. V. Computing chemistry on the web Drug Discovery Today 2005, 10, 1497-1500
60. Tetko, I. V.; Tanchuk, V. Y. Application of associate neutral networks for prediction of lipophilicity in ALOGPS 2.1 program J. Chem. Inf. Comput. Sci. 2002, 42, 1136-1145
61. Tetko, I. V.; Tanchuk, V. Y.; Villa, A. E. Prediction of n -octanol/water partition coefficients from PHYSPROP database using artificial neural networks and E-state indices J. Chem. Inf. Comput. Sci. 2001, 41, 1407-1421
62. Tetko, I. V.; Tanchuk, V. Y.; Kasheva, T. N.; Villa, A. E. Estimation of aqueous solubility of chemical compounds using E-state indices J. Chem. Inf. Comput. Sci. 2001, 41, 1488-1493
63. Smith, L. R.; Mahoney, N.; Molyneux, R. J. Synthesis and structure-phytotoxicity relationships of acetylenic phenols and benzopyrane metabolites, and their analogues, from the grapevine pathogen Eutypa lata J. Nat. Prod. 2003, 66, 169-176
64. Roblin, R. O., Jr.; Clapp, J. W. The preparation of heterocyclic sulfonamides J. Am. Chem. Soc. 1950, 72, 4890-4892
65. Karino, H.; Goda, H.; Sakamoto, J.; Yoshida, K.; Nishiguchi, H. Process for preparing aromatic or heteroaromatic sulfonyl halides. U.S. patent 5,811,571. Sep 22, 1998.
66. Wright, S. W.; Hallstrom, K. N. A Convenient preparation of heteroaryl sulfonamides and sulfonyl fluorides from heteroaryl thiols J. Org. Chem. 2006, 71, 1080-1084
67. Hanessian, S.; Kagotani, M.; Komaglou, K. Design and reactivity of organic functional groups-2-Pyridylsulfonates as nucleofugal esters: Remarkably mild transformations into halides and olefins Heterocycles 1989, 28, 1115-1120
68. Diltz, S.; Aguirre, G.; Ortega, F.; Walsh, P. J. Synthesis of chiral heteroaromatic tetradentate sulfonamide based ligands Tetrahedron: Asymmetry 1997, 8, 3559-3562
69. Crombie, L.; Bandaranayake, W. M.; Whiting, D. A. 2-Hydroxy-3-methyl-1,1- dimethoxybutane, new reagent for dimethylbenzopyranylation. Synthesis of lonchocarpin, jacareubin, evodionol methyl ether, and other benzopyranes J. Chem. Soc. (C) 1971, 4, 811-816
70. Crombie, L.; Bandaranayake, W. M.; Whiting, D. A. Novel methods for the synthesis of 2,2-dimethylbenzopyranes J. Chem. Soc. (D), Chem. Commun. 1969, 17, 970-971
71. Henry, G. E.; Jacobs, H. A short synthesis of 5-methoxy-2,2-dimethyl-2 H -1-benzopyran-6-propanoic acid methyl ester Tetrahedron 2001, 57, 5335-5338
72. Rodriguez-Lopez, V.; Moreno-Escobar, J. A.; Avila-Torres, O.; Tlahuext, H. 6-Acetyl-5-hydroxy-2,2-dimethyl-2 H -chromene Acta Crystallogr. 2006, E62, o3616-o3617
73. Orgala, J.; Erdelmeier, C. A. J.; Wright, A. D.; Rali, T.; Sticher, O. Two chromenes and a prenylated benzoic acid derivative from Piper aduncum Phytochemistry 1993, 34, 813-818
74. Batista, J. M., Jr.; Lopes, A. A.; Ambrosio, D. L.; Regasini, L. O.; Kato, M. J.; Bolzani, V. S.; Cicarelli, R. M. B.; Furlan, M. Natural chromenes and chromene derivatives as potential anti-trypanosomal agents Biol. Pharm. Bull. 2008, 31, 538-540
75. Johnson, A. J.; Kumar, R., A.; Rasheed, S. A.; Chandrika, S. P.; Chandrasekhar, A.; Baby, S.; Subramoniam, A. Antipyretic, analgesic, anti-inflammatory and antioxidant activities of two major chromenes from Melicope lunu-ankenda J. Ethnopharmacol. 2010, 130, 267-271
76. Dragovich, P. S.; Prins, T. J.; Zhou, R.; Johnson, T. O.; Hua, Y.; Luu, H. T.; Sakata, S. K.; Brown, E. L.; Maldonado, F. C.; Tuntland, T.; Lee, C. A.; Fuhrman, S. A.; Zalman, L. S.; Patick, A. K.; Matthews, D. A.; Wu, E. Y.; Guo, M.; Borer, B. C.; Nayyar, N. K.; Moran, T.; Chen, L.; Rejto, P. A.; Rose, P. W.; Guzman, M. C.; Dovalsantos, E. Z.; Lee, S.; Gleeson, J.-P. R.; Wu, Z. P.; Liu, J.; Meador, J. W., III; Ferre, R. A. Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 8. Pharmacological optimization of orally bioavailable 2-pyridone-containing peptidomimetics J. Med. Chem. 2003, 46, 4572-4585
77. Perez, R. P.; Godwin, A. K.; Handel, L. M.; Hamilton, T. C. A. Comparison of clonogenic, microtetrazolium and sulforhodamine B assays for determination of cisplatin cytotoxicity in human ovarian carcinoma cell lines Eur. J. Cancer 1993, 29A, 395-399
78. Vichai, V.; Kirtikara, K. Sulforhodamine B colorimetric assay for cytotoxicity screening Nat. Protocols 2006, 3, 1112-1116