Structure‐function activity of azasterols and nitrogen‐containing steroids

Kabara, Jon J.; Holzschu, Donald L.; Catsoulacos, Demokri Tos P.

doi:10.1007/bf02533051

Cited by 15 publications

(2 citation statements)

References 44 publications

(27 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our theoretical research supports early studies on the action mechanisms of amino and azasteroids that was presumed that these compounds act due to a more fundamental mode than on sterol metabolism alone, interfering with mitochondrial respiration and/or oxidative phosphorylation [41]. Computer modeling prediction of steroidal compounds metabolism by CYP3A4 with has been documented in several studies [42][43][44].…”

Section: Discussionsupporting

confidence: 59%

Lactandrate: a D-homo-aza-androsterone alkylator in the treatment of breast cancer

Trafalis

Geromichalos

Koukoulitsa

et al. 2005

Breast Cancer Res Treat

View full text Add to dashboard Cite

The sensitivity of breast neoplasms to hormonal control provides the basis of novel investigational treatments with steroidal alkylators. An androsterone D-lactam steroidal ester, the 3beta-hydroxy-13alpha-amino-13,17-seco- 5alpha-androstan-17-oic-13,17-lactam, p-bis(2-chloroethyl)amino phenyl acetate (lactandrate) was synthesized and tested for antitumor activity against six human breast cancer cell lines in vitro and against two murine and one xenograft mammary tumors in vivo. A docking study on the binding interactions of lactandrate with the ligand-binding domain (LBD) of estrogen receptor-alpha (ERalpha) was inquired. In vitro testing of lactandrate cytostatic and cytotoxic activity was performed on T47D, MCF7, MDA-MB-231, BT-549, Hs578T, MDA-MB-435 breast adenocarcinoma human cell lines. In vivo testing was performed on two murine mammary tumors, the MXT tumor and CD8F1 adenocarcinoma, as well as on human mammary carcinoma MX-1 xenograft. Molecular modeling techniques were adopted to predict a possible location and interaction mode of the molecule into LBD. Lactandrate induced significantly high antitumor effect against all tested in vitro and in vivo models. The cell lines with positive ER expression found to be significantly more sensitive to lactandrate. Moreover, lactandrate found to be positioned inside the binding cavity with its steroidal moiety, whilst the alkylating moiety protrudes out of receptor's pocket. Lactandrate produced important anticancer activity on breast cancer in vitro and in vivo. Some correlation between ER and lactandrate effect was demonstrated. Docking studies provide the basis for the structure-based design of improved steroidal alkylating esters for the treatment of estrogen-related cancers.

show abstract

Section: Discussionsupporting

confidence: 59%

Lactandrate: a D-homo-aza-androsterone alkylator in the treatment of breast cancer

Trafalis

Geromichalos

Koukoulitsa

et al. 2005

Breast Cancer Res Treat

View full text Add to dashboard Cite

show abstract

“…In early studies on the action mechanisms of amino and azasteroids it was presumed that these compounds act because of a more fundamental mode than on sterol metabolism alone, interfering with mitochondrial respiration and/or oxidative phosphorylation (Kabara et al , 1976). Trafalis et al (1995) first reported the stimulatory effect of two steroid lactams (homo‐aza‐steroids) on the proliferation of non‐lymphocytic leukaemia blast cells that possibly was produced through PKC system induction.…”

Section: Discussionmentioning

confidence: 99%

Preclinical studies on NSC290205 aza‐steroid alkylator activity in combination with adriamycin against lymphoid leukaemia

Trafalis

Tsavdaridis²,

Camoutsis

et al. 2005

Br J Haematol

View full text Add to dashboard Cite

Summary NSC290205 (A) is an hybrid synthetic antineoplastic ester that is a combination of a d-lactam derivative of androsterone and an alkylating derivative of N,N-bis(2-chloroethyl)aniline. We tested NSC290205 for synergistic antileukaemic activity with adriamycin (ADR), (i) in vitro against the human lymphoid leukaemia cell lines: CCRF-CEM, MOLT-4, and RPMI-8226, (ii) in vivo against P388 lymphocytic and L1210 lymphoid murine leukaemias (at incipient and advanced phase). Our results indicated significant cytostatic and cytotoxic synergy of NSC290205 and ADR in vitro. We further examined these results in vivo by replacing cyclophosphamide in the standard CHOP (cyclophosphamide, hydroxydaunomycin, Oncovin, prednisone) regimen with NSC290205 (AHOP) and comparing the efficiency of these two regimens in vivo. Although treatment of P388 and L1210 with cyclophosphamide or NSC290205 alone yielded equivalent results, AHOP produced a clear benefit for survival compared with CHOP against advanced leukaemias, confirming the in vitro observations [higher percentage increase in median lifespan of treated animals over the untreated (control): 188% and 239% in L1210, 308% and 353% in P388, P < 0AE01, for CHOP and AHOP respectively]. AHOP also proved to be more genotoxic and cytostatic than CHOP, inducing higher sister chromatid exchange levels and cell division delays on P388 cells in vivo. NSC290205 showed superior antineoplastic potential against lymphoid leukaemia and significant synergy with ADR, producing an excellent therapeutic outcome.

show abstract

Azachrysene preparation

Hearn

SWANSON

1981

Journal of Heterocyclic Chem

View full text Add to dashboard Cite

Structure‐function activity of azasterols and nitrogen‐containing steroids

Cited by 15 publications

References 44 publications

Lactandrate: a D-homo-aza-androsterone alkylator in the treatment of breast cancer

Lactandrate: a D-homo-aza-androsterone alkylator in the treatment of breast cancer

Preclinical studies on NSC290205 aza‐steroid alkylator activity in combination with adriamycin against lymphoid leukaemia

Azachrysene preparation

Contact Info

Product

Resources

About