Novel Antiproliferative Agents Derived from Lavendustin A

Nußbaumer, Peter; Ap, Winiski; Cammisuli, Salvatore; Hiestand, Peter; Weckbecker, Gisbert; Stütz, Anton

doi:10.1021/jm00050a005

Cited by 28 publications

(28 citation statements)

References 11 publications

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“…SDZ 281-977 was demonstrated to be the most potent antiproliferative agent of this series when tested against a large panel of tumor cell lines in vitro (Nussbaumer et al, 1994~).…”

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confidence: 99%

SDZ 281-977: A modified partial structure of lavendustin A that exerts potent and selective antiproliferative activitiesin vitro andin vivo

Cammisuli

Winiski²,

Nußbaumer³

et al. 1996

Int. J. Cancer

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The chemical derivatization of biologically active microbial metabolites continues to be a promising approach to the identification of new drugs. We recently synthesized the novel antiproliferative compound SDZ 28 I-977,5-12-(2,5-dimethoxy-phenyl)ethyl]-2-hydroxy-benzoic acid methylester, a derivative of the EGF receptor tyrosine kinase inhibitor lavendustin A. Here we report on our studies of the anticancer efficacy and the mode of action of SDZ 28 1-977. The growth of both the human pancreatic tumor cells MIA PaCa-2 and the human vulvar carcinoma cells A431 was inhibited in the low micromolar range. Tumors from these cells were induced in nude mice and were shown to respond to orally or intravenously administered SDZ 28 1-977. In contrast, no antitumor effect was detected in rats bearing dimethylbenzanthracene-induced mammary tumors. Studies in mice indicated that SDZ 281-977 was neither immunosuppressive nor hematosuppressive at doses effectively inhibiting tumor growth. Surprisingly, the mode of action of SDZ 281-977 apparently does not involve inhibition of EGF receptor tyrosine kinase, because, in contrast to lavendustin A, SDZ 281-977 failed to inhibit this enzyme in a cell-free assay. The mechanism of the antiproliferative effect can be explained on a cellular level by the ability of the compound to arrest cells in mitosis. SDZ 28 1-977 is thus the first example of an antimi-totic agent derived from the potent tyrosine kinase inhibitor lavendustin A. The therapeutic potential of SDZ 281-977 is enhanced by the fact that it is not subject to multidrug resistance, because tumor cells expressing the multidrug resistance phenotype were as sensitive to SDZ 281-977 as their nonresistant counterparts. In conclusion, SDZ 28 1-977 represents a novel lavendustin A derivative with potent antiprolifera-tive properties in vitro and in vivo that may be explained on the basis of its antimitotic effects. SDZ 28 1-977 may be a candidate drug for the treatment of selected cancers, including those expressin the multidrug resistance phenotype. o 1996 Wf?y-Liss, Inc.

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“…SDZ 281-977 was demonstrated to be the most potent antiproliferative agent of this series when tested against a large panel of tumor cell lines in vitro (Nussbaumer et al, 1994~).…”

mentioning

confidence: 99%

SDZ 281-977: A modified partial structure of lavendustin A that exerts potent and selective antiproliferative activitiesin vitro andin vivo

Cammisuli

Winiski²,

Nußbaumer³

et al. 1996

Int. J. Cancer

Self Cite

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“…2), and only slight differences indicated by the alkyl chains are shown; the number of unsaturated bonds and methylene groups affects the hydrophobicity of the molecule, which plays an important role in the interaction between small molecule drugs and proteins. [28][29][30][31] The higher molecular weight and unsaturation of daucosterol compared to the other two saponins could be related to its strongest inhibition. Moreover, daucosterol was the most abundant saponin isolated from Eleocharis dulcis peel, indicating that it was the major a-glucosidase inhibitory factor in the saponin fraction.…”

Section: A-glucosidase Inhibitory Activitymentioning

confidence: 99%

Inhibitory properties of saponin from Eleocharis dulcis peel against α-glucosidase

Yang

Shang

et al. 2021

RSC Adv.

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“…The discrepancy was attributed to poor cellular permeability resulting from the multiple polar groups and high polar surface area of 122 . Medicinal chemistry efforts to improve cellular penetration and antiproliferative activity of 122 were initiated . The partial structure 123 was prepared, in which the o ‐cresol moiety was removed to decrease polarity, however, it was still inactive in cells.…”

Section: Development Of Anticancer Drugs or Drug Candidates From Natumentioning

confidence: 99%

Strategies for the Optimization of Natural Leads to Anticancer Drugs or Drug Candidates

Xiao

Morris‐Natschke

Lee

2015

Medicinal Research Reviews

143

100

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Natural products have made significant contribution to cancer chemotherapy over the past decades and remain an indispensable source of molecular and mechanistic diversity for anticancer drug discovery. More often than not, natural products may serve as leads for further drug development rather than as effective anticancer drugs by themselves. Generally, optimization of natural leads into anticancer drugs or drug candidates should not only address drug efficacy, but also improve ADMET profiles and chemical accessibility associated with the natural leads. Optimization strategies involve direct chemical manipulation of functional groups, structure-activity relationship-directed optimization and pharmacophore-oriented molecular design based on the natural templates. Both fundamental medicinal chemistry principles (e.g., bio-isosterism) and state-of-the-art computer-aided drug design techniques (e.g., structure-based design) can be applied to facilitate optimization efforts. In this review, the strategies to optimize natural leads to anticancer drugs or drug candidates are illustrated with examples and described according to their purposes. Furthermore, successful case studies on lead optimization of bioactive compounds performed in the Natural Products Research Laboratories at UNC are highlighted.

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Novel Antiproliferative Agents Derived from Lavendustin A

Cited by 28 publications

References 11 publications

SDZ 281-977: A modified partial structure of lavendustin A that exerts potent and selective antiproliferative activitiesin vitro andin vivo

SDZ 281-977: A modified partial structure of lavendustin A that exerts potent and selective antiproliferative activitiesin vitro andin vivo

Inhibitory properties of saponin from Eleocharis dulcis peel against α-glucosidase

Strategies for the Optimization of Natural Leads to Anticancer Drugs or Drug Candidates

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