The preparation and anticancer activity of some phosphorus heterocycles

Article abstract of DOI:10.1080/10426500801938592

Methods for the preparation of some phosphorus heterocycles are reviewed, together with a preliminary report of their activity in vitro against the NCI 60-cell line panel of human tumour cells. The most active compound, a dimer of 3-methyl-1-(2,4,6-triisopropylphenyl)phosphole oxide, showed GI50 values in the micromolar region against leukaemia cell lines RPMI-8226 and SR, non-small cell lung cancer (NCI-H460), colon cancer (COLO 205), and melanoma (SK-Mel-5 and UACC-62). Copyright Taylor & Francis Group, LLC.

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Phosphorus, Sulfur, and Silicon
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The Preparation and
Anticancer Activity of Some
Phosphorus Heterocycles
Harry R. Hudson a & György Keglevich b
a Department of Health and Human Sciences ,
London Metropolitan University , London, UK
b Department of Organic Chemistry and Technology ,
Budapest University of Technology and Economics ,
Budapest, Hungary
Published online: 12 Aug 2008.
To cite this article: Harry R. Hudson & György Keglevich (2008) The Preparation and
Anticancer Activity of Some Phosphorus Heterocycles, Phosphorus, Sulfur, and Silicon
and the Related Elements, 183:9, 2256-2261, DOI: 10.1080/10426500801938592
To link to this article: http://dx.doi.org/10.1080/10426500801938592
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Phosphorus, Sulfur, and Silicon, 183:2256–2261, 2008
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500801938592
The Preparation and Anticancer Activity of Some
Phosphorus Heterocycles
1
2
¨
Harry R. Hudson and Gyorgy Keglevich
1Department of Health and Human Sciences, London Metropolitan
University, London, UK
2Department of Organic Chemistry and Technology, Budapest
University of Technology and Economics, Budapest, Hungary
Methods for the preparation of some phosphorus heterocycles are reviewed, together
with a preliminary report of their activity in vitro against the NCI 60-cell line
panel of human tumour cells. The most active compound, a dimer of 3-methyl-1-
(2,4,6-triisopropylphenyl)phosphole oxide, showed GI values in the micromolar
50
region against leukaemia cell lines RPMI-8226 and SR, non-small cell lung cancer
(NCI-H460), colon cancer (COLO 205), and melanoma (SK-Mel-5 and UACC-62).
Keywords Anticancer; dihydrophosphinine; NCI; organophosphorus; phosphanor-
bornene; phosphole oxide; phosphorus heterocycle; tetrahydrophosphinine
INTRODUCTION
Chemotherapy is an important aspect of the treatment of cancer.1
The numbers and types of compound that have been reported to
show anticancer activity are legion and numerous new examples
are constantly under investigation.2 Those that have become estab-
lished in clinical use3 include organophosphorus compounds such
as cyclophosphamide4 (a nitrogen mustard) and related phospho-
ramide derivatives such as ifosfamide and thiotepa, all of which act
as alkylating agents and cause DNA cross-linking.5 Other types of
organophosphorus compound that exhibit anticancer activity include
various phosphonic and phosphinic acid derivatives,6 e.g., nucleoside
phosphonates,5 aminophosphonates,7 bisphosphonic acid derivatives,8
Received 17, January 2008; accepted 20, January 2008.
We thank the National Cancer Institute11 for anticancer screening and for the bio-
logical data reported in this paper. This project was also supported by the Hungarian
Scientific Research Fund (OTKA Grant No. T067679).
Address correspondence to Gyo¨rgy Keglevich, Department of Organic Chemistry and
Technology, Budapest University of Technology and Economics, Budapest 1521, Hungary.
E-mail: keglevich@mail.bme.hu
2256

Anticancer Activity of Phosphorus Heterocycles
2257
SCHEME 1
phosphonocarboxylate-platinum complexes,9 and aminophosphonate-
platinum complexes.10
We report here an overview of the preparation and activity of the
phosphole oxide derivatives 3 and 5, and of a number of dihydrophos-
phinines (8a-c and 13a,c-e) and tetrahydrophosphinines (14f-h and
15), which have been subjected to in vitro screening at the National
Cancer Institute (NCI).11 Anticancer activity has not previously been
reported for compounds of these types.
SYNTHETIC METHODS
In the last two decades, a number of families of phosphorus heterocycles
have been described.12,13
Within the group of 7-phosphanorbornene derivatives, the phosphole
oxide dimer 3 with sterically demanding 2,4,6-triisopropylphenyl sub-
stituents at the phosphorus atoms was prepared. The phosphole 1 was
converted to the corresponding phosphole oxide 2, which underwent a
regio- and stereospecific dimerization to afford product 3 (Scheme 1).14
2,5-Dihydro-1H-phosphole oxides 4 and 6a-c were subjected to dichloro-
carbene addition to give 3-phosphabicyclo[3.1.0]hexane 3-oxides 5
and 7a-c, respectively, in both cases as a mixture of two diastere-
omers (Schemes 2 and 3).15,16 The opening of the cyclopropane ring
SCHEME 2

2258
H. R. Hudson and G. Keglevich
SCHEME 3
of dichlorocarbene adducts 7a-c led to the predominant formation of
1,2-dihydrophosphinine 1-oxides 8a-c (Scheme 3).16
The dichlorocarbene addition reaction of 3,4-dimethyl-2,5-
dihydro-1H-phosphole oxides 9a,c-e furnished surprisingly the 4-
dichloromethylene-1,4-dihydrophosphinine oxides 13a,c-e (Scheme 4).
In this instance, the 3-phosphabicyclo[3.1.0]hexane oxide 10a,c-e
underwent a spontaneous cyclopropane ring opening to provide
1,2-dihydrophosphinine oxide 11. The latter underwent a dichloro-
cyclopropanation to give 12, which afforded 13 by cyclopropane ring
opening and the loss of hydrogen chloride.17
Diethyl phosphite and diphenylphosphine oxide were added to the
electron-poor double-bond of 1,2-dihydrophosphinine oxides 8a and 8e
after activation with trimethylaluminum. Products of the phospha-
Michael reaction were the 3-phosphonato- and 3-diphenylphosphin-
oxido-1,2,3,6-tetrahydrophosphinine oxides 14f,g and 14h, respectively
(Scheme 5).18 The addition was diastereoselective. Hydrogenolysis of
the dibenzyl ester (14, Y Et, Z BnO) gave the phosphonic acid 15.18
SCHEME 4

Anticancer Activity of Phosphorus Heterocycles
2259
SCHEME 5
ANTICANCER ACTIVITY
Compounds 3, 5, 8a-c and 13a,c-e were tested in vitro against the NCI
60-cell line panel of human tumour cells at a maximum concentration
level of 10−4 molar, and at four lower concentrations, each at successive
10-fold dilutions down to 10−8 molar. The results, which are summa-
rized in Table I, show average response parameters over all cell lines of
GI50 between 2.1 × 10−6 and 7.32 × 10−5 M, TGI between 6.63 × 10−6
and 9.84 × 10−5 M, and LC50 between 2.7 × 10−6 and 1.0 × 10−4 M. The
most active compound overall was the phosphanorbornene derivative 3
for which GI50 values in the region of 1–1.5 × 10−6 molar were recorded
in duplicate experiments against leukaemia cell lines RPMI-8226 and
TABLE I Anticancer Activity in 60 Cell Line 5-Dose Screening for
Compounds 3, 5, 8, 13, 14a
Average over all cell lines (M)b
GI50
TGI
LC50
3
5
2.10 × 10−6
8.66 × 10−6
1.48 × 10−5
3.30 × 10−5
7.32 × 10−5
1.06 × 10−5
4.71 × 10−5
7.50 × 10−6
6.13 × 10−6
6.63 × 10−6
2.16 × 10−5
3.81 × 10−5
7.48 × 10−5
9.84 × 10−5
4.58 × 10−5
8.67 × 10−5
2.92 × 10−5
2.37 × 10−5
2.70 × 10−6
5.27 × 10−5
7.46 × 10−5
9.48 × 10−5
1.00 × 10−4
8.81 × 10−5
9.60 × 10−5
7.64 × 10−5
7.08 × 10−5
8a
8b
8c
13a
13c
13d
13e
aData from the DTP website (http://dtp.nci.nih.gov), where full information is given
for compounds 3 (NSC 709166), 5 (NSC 709160), 8a (NSC 639390), 8b (NSC 644257),
8c (NSC 639391), 13a (NSC 644259), 13c (NSC 648099), 13d (NSC 648100), and 13e
(NSC 624332).
bMolar concentrations for 50% growth inhibition (GI50), total growth inhibition
(TGI), and 50% kill (LC50).

2260
H. R. Hudson and G. Keglevich
TABLE II Percentage Growth (Relative to Control) in One Dose 60
Cell Line Assay for Compounds 14 and 15, at Single Dose Level of
10−5 Ma
Leukemia CCRF-CEM
Leukemia HL-60 (TB)
Renal cancer UO-31
14f
14g
14h
15
−27.48
−90.63
47.59
−35.59
—
—
28.77
11.46
—
—
—
42.48
aNegative values indicate the level of kill. Positive values indicate growth inhibition
by at least 50%.
SR, non-small cell lung cancer (NCI-H460), colon cancer (COLO 205),
and melanoma (SK-Mel-5 and UACC-62). The mode of action is not
known. Attempts to gain an insight into possible mechanisms of action
by means of the NCI program COMPARE19 revealed no satisfactory
correlations with standard agents.
One dose 60 cell line assay was carried out at a concentration of 10−5
molar for the tetrahydrophosphinines 14f-h and 15, which were found
to be less active. In most cases the percent growth was not changed
significantly under these test conditions but some exceptions, for which
limited activity was detected, are shown in Table II.
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