Depending on what you want to do, you actually have a few possible frameworks :
[Django] Big, strong (to the limit of what a python framework can be), and the older in the race. Used by a few 'big' sites around the world ([Django sites]). Still is a bit of an overkill for almost everything and with a deprecated coding approach.
[Turbogears] is a recent framework based on Pylons. Don't know much about it, but got many good feedbacks from friends who tried it.
[Pylons] ( which Turbogears2 is based on ). Often saw at the "PHP of Python" , it allow very quick developements from scratch. Even if it can seem inappropriate for big projects, it's often the faster and easier way to go.
The last option is [Zope] ( with or without Plone ), but Plone is way to slow, and Zope learning curve is way too long ( not even speaking in replacing the ZODB with an SQL connector ) so if you don't know the framework yet, just forget about it.
And yes, An ORM seem mandatory for a project of this size. For Django, you'll have to handle migration to their database models (don't know how hard it is to plug SQLAlchemy in Django). For turbogears and Pylons, the most suitable solution is [SQLAlchemy], which is actually the most complete ( and rising ) ORM for python. For zope ... well, nevermind
Last but not least, I'm not sure you're starting on a good basis for your project. 500 tables on any python framework would scare me to death. A boring but rigid language such as java (hibernate+spring+tapestry or so) seem really more appropriate.